E2(P_€l‘t
`OPINION
`A
`l::::l:li:l::tachykinin
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`2:
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`receptors and the emetic reflex
`3. Tachykinin NK1 receptor
`antagonists
`4. Expert opinion
`
`Review
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`Monthly Focus: Oncologic, Endocrine & Metobolic
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`Tachykinin NK1 receptor
`antagonists for the control of
`chemotherapy-induced nausea
`and vomiting
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`Jeremy D Cale. Brian T O'Neill & John M Humphrey
`Pfizer Global Rtzmrrh & Development. Deparrmancr JDl'.\1.'0VEI)’ Bialag}: Sandwich, Kent. UK’ Pfizer
`Clabal Il’es:'aIz‘lr & Q-ielopment, Department 0//l'fi=dla'naI Chemistry; Cmmn, CT U94
`
`The treatment of neoplastic disease with chemotherapeutic cytotoxic drugs
`has long been associated with profound nausea and vomiting (emesis). This
`became the most feared side effect of this type of treatment and was so
`severe that some patients would withdraw from further treatment, thus
`jeopardising their clinical outcome and possibly life expectancy. The introduc-
`tion of the 5-HT, receptor antagonists had a significant impact in this area,
`offering substantial reductions in emesis, largely through prophylactic treat-
`ment. Unfortunately, some forms of emesis were resistant to treatment with
`these drugs, so the search has continued to identify new chemical entities
`with a higher level of efficacy and a broader spectrum of activity. Data gener-
`ated in animals has identified tachykinin NK1 receptors as highly important in
`the emetic reflex and experimental evidence strongly supports NK, receptor
`antagonists as highly efficacious anti-emetic agents. with unparalleled broad
`spectrum activity. Several novel antagonists have recently entered clinical
`development and data are emerging to support their anti-emetic activity.
`This area continues to attract substantial medicinal chemical research effort.
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`Most major pharmaceutical companies are seeking new matter through
`structural refinement of early leads or discovery of novel compounds from
`library screening. The scope of chemical lead matter has advanced from early
`piperidine and quinuclidines to a spectrum of templates that improve expec-
`tations for a well-tolerated therapeutic agent. Recent success in combining
`5-HT, and NK, antagonists in emesis treatment is expected to greatly advance
`clinical outcomes with newer and safer agents.
`
`Keywords: emesis. nausea. NK,. substance P. tachykinin. tachykinin receptor antagonist. vomiting
`
`gem opm. mr. em.-my (2001) 11//2).-/337-1347
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`1. Introduction
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`The introduction of the 5-HT3 receptor antagonists revolutionised the treatment of
`emesis associated with cancer treatment with cytotoxic chemotherapeutic agents.
`Until this date, intractable nausea and vomiting had become a common feature
`associated with many chemotherapy regimens, particularly those that
`included
`highly-emetogenlc platinum-containing compounds. such as cisplatin. Prior to the
`launch of the prototypical 5-HT3 receptor antagonist ondansetron. treatment of
`these troublesome adverse events was based on high doses of metoclopramlde. antip-
`sychotic agents such as chlorpromazine and haloperidol and iv. benzodiazepines,
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`A agents whose use was fraught with problematic side effects.
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`sedation and dyskinesias.
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`including profound
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`Ashley Publications
`www.ashley-pub.com
`
`2001 0 Ashley Publications nu ISSN 1354-3775
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`1831
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`Page 1 of 11
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`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Helsinn Healthcare Exhibit 2031
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`

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`Tachykinin NK1 receptor antagonists for the control of chemotherapy-induced nausea and vomiting
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`this
`Whilst
`class of agents was
`the introduction of
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`undoubtedly a significant step forward, a number of features
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`of the emetic response to chemotherapy regimens proved
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`resistant to treatment. Specifically, whilst the degree of control
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`of vomiting on day one of the first cycle of chemotherapy was
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`impressive, the maximum efficacy of the 5—HT3 antagonists
`was found to diminish upon subsequent cycles of treatment.
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`Delayed emesis, primarily seen 2 days following treatment
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`and lasting for 3 or more days, was also difficult to control
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`with this class of agent [1]. The efficacy of the 5—HT3 receptor
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`antagonists in controlling nausea has been less impressive than
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`their control of vomiting, with complete control of nausea
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`being commonly achieved in only 50% of patients. ln spite of
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`recent attempts to arrive at consensus regarding optimal
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`doses, dosing schedules and routes of administration for these
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`agents [2], this remains the most troublesome side effect cur-
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`rently reported by patients undergoing chemotherapy.
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`Although of less direct relevance to this review, the 5—HT3
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`antagonists are also used for the treatment or prophylaxis of
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`post—operative nausea and vomiting. Whilst these agents have
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`some, albeit modest, efficacy in this indication [3], there are
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`few data that demonstrate clear superiority over older agents,
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`including the dopamine receptor antagonists [4]. The 5—HT3
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`antagonists are also poorly effective at treating emesis associ-
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`ated with treatment with opioid analgesics [5] or emesis associ-
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`ated with perturbations of the vestibular system, including
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`motion sickness [6]. Clearly, the sub—optimal anti—emetic pro-
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`file of the 5-HT3 receptor antagonists creates an opportunity
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`to identify and develop superior agents with greater efficacy
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`and a broader spectrum of activity.
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`The precise locus for the anti—emetic activity of the 5—HT3
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`receptor antagonists remains unclear. There is still debate over
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`whether the most important site of receptor blockade lies
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`within the central or the peripheral nervous system, or indeed
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`whether receptor blockade at both sites is important. What is
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`clear, however, is that many chemotherapeutic agents evoke a
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`significant
`release of 5-HT from enterochromaffin cells
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`within the wall of the small intestine. 5-HT thus released
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`stimulates 5—l—lT3 receptors located on afferent nerve fibres of
`the vagus nerve that project
`into dorsomedial medullary
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`structures in the brainstem. These sensory fibres also appear
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`to have 5-HT3 receptors on their central
`terminals, which
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`modulate the release of neurotransmitters in this region and
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`may representfa further site of drug activity. Considering these
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`sites of drug action, one option for producing agents with
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`greater efficacy and potentially a broader spectrum of activity
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`would be to identify a drug target sitting at a more central site
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`in the emetic reflex, ideally at a site of convergence for the
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`processing of sensory information.
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`2. Tachykinins, tachykinin receptors and the
`emetic reflex
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`The tachykinins are a family of peptide neurotransmitters that
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`includes substance P, neurokinin A and neurokinin B. These
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`peptides interact specifically with a family of membrane—asso—
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`ciated G-protein coupled receptors termed NK1, NK2 and
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`NK3. A fourth member of this receptor family has been
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`found, NK4 [7,8], but the precise nature of this receptor has yet
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`to be elucidated. Substance P has the highest affinity for NK1
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`receptors, neurokinin A the highest affinity for NK2 receptors
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`and neurokinin B the highest affinity for NK3 receptors.
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`However,
`this selectivity is not absolute and the potential
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`exists for these ligands to interact with any member of the
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`receptor family.
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`2.1 Anatomy
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`Neuroanatomical studies have demonstrated substance P
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`immunoreactivity in numerous structures within the human
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`brainstem, including the dorsal motor nucleus of the vagus
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`nerve, the reticular formation and the nucleus of the solitary
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`tract [911]. These nuclei are of major significance in the physi-
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`ology of the emetic reflex. Complementary to these data,
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`autoradiographic analysis has localised tachykinin NK1 recep-
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`tors to many of the same regions [12]. To date, no studies of
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`human brainstem have investigated the distribution of either
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`neurokinin A or neurokinin B in any of the regions and nuclei
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`of the implicated in the emetic reflex. Similarly, the localisa-
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`tion of tachykinin NK2 and NK3 receptors in the nuclei of the
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`human brainstem has not yet been studied.
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`2.2 Pharmacology
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`lt has been known for many years from work in animals that
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`substance P can evoke neuronal excitation in the area pos-
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`trema of the dorsal brainstem [13]. This region lies at the base
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`of the fourth cerebral ventricle and is in close apposition to
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`the nucleus of the solitary tract. These regions receive dense
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`afferent projection from the proximal Gl tract and are funda-
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`mentally important in the emetic reflex. lt might be expected
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`that any agent which excites neurones in these regions could
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`evoke emesis and this has been shown to be the case in dogs,
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`where iv. administration of substance P evokes vomiting [14].
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`Data generated in ferrets also supports a role for tachykinin
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`receptors in eliciting the emetic reflex, with the selective NK1
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`receptor agonist, GR7363Z evoking a profound emetic
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`response following intracerebroventricular administration [15].
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`»These data raise the possibility that the tachykinin NK1 recep-
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`tor is involved in the emetic reflex and moreover, if the site of
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`action is within the CNS, that it represents a convergent tar-
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`get for diverse emetogenic inputs.
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`The value of this hypothesis relies on being able to demon-
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`strate that selective tachykinin receptor antagonists can modu-
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`late the emetic response to clinically relevant emetogens. A
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`number of studies, primarily by scientists from Pfizer, Glaxo
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`Wellcome
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`strated this in animals unequivocally. ln the ferret, the proto-
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`dose-
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`typical NK1
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`CP—99,994,
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`dependently inhibited the emetic response to cisplatin. This
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`effect could be mimicked by administration of the compound
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`at lower doses directly to the brain, suggesting a central site of
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`1838
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`Page2of11
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`Expert Opin. Then Parents (2001) 11(12)
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`Page 2 of 11
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`action,
`implicated by earlier work with the agonist,
`as
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`GR73632 and the peptide antagonist GR82334 [15,16]. Impor-
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`tantly, CP—l00,263,
`the inactive enantiomer of CP—99,994,
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`was inactive against cisplatin—induced emesis in the ferret, con-
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`firming the NK1 receptor—mediated nature of the emetic
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`response [17]. The central site of action has been confirmed
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`with data obtained using agents that very poorly penetrate the
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`blood—brain barrier
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`antagonist L—743,3l0 is inactive against an emetic challenge
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`with cisplatin, unless it is given centrally when it completely
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`blocks the emetic response. More recently, direct microinjec—
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`tion of the highly potent NK1 antagonist GR205l7l into dis-
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`crete nuclei of the brainstem has confirmed that, at least in
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`dogs, NK1 receptors in an area adjacent dorsally to the nucleus
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`ambiguus represent a likely site of action [19].
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`the NK1 receptor
`Subsequent
`to these seminal studies,
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`antagonists have been shown to have an unprecedented broad
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`spectrum of anti-emetic activity in a very wide range of ani-
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`mal species, including the dog, ferret, cat, pig and shrew. Spe-
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`cifically, NK1 receptor antagonists prevent emetic responses to
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`chemotherapeutic agents
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`responses), radiation, volatile and gaseous anaesthetic agents,
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`ipecacuanha, morphine, ethanol, copper sulfate and motion.
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`These data are particularly exciting because they include
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`agents and stimuli that have been refractory to anti—emetic
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`treatment with 5—HT3 antagonists in both animals and, more
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`importantly, man.
`ln particular,
`in two animal models of
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`delayed emesis, the NK1 receptor antagonists L-754,030 (and
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`its prodrug, L-758,298), GR205l7l, PD 154075 and CP-
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`99,994 have all been demonstrated to inhibit the delayed
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`emetic response to cisplatin in ferrets and piglet [20-23].
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`2.3 Clinical data
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`A number of NK1 receptor antagonists have progressed to
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`clinical trial for determination of their anti-emetic efficacy in
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`a clinical setting. In a study of cisplatin—induced emesis, addi-
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`tion of the Pfizer NK1 receptor antagonist, C]-l 1,974 (E210-
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`pitant),
`to an anti-emetic regime comprising the 5—HT3
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`antagonist granisetron and dexamethasone was superior to use
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`of the 5—l—lT3 antagonist and steroid alone [24]. In this study,
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`both acute (day 1) and delayed (days 2 to 5) emesis were sig-
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`nificantly better controlled than when a regime of standard
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`care was employed. Significantly, nausea was also better con-
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`trolled in the patient group treated with C]-11,974. Similar
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`data has also been generated from a study with the Merck
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`NK1 antagonist, L-754,030 [25]. The anti-emetic efficacy of
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`the NK1 antagonists has been confirmed in subsequent stud-
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`ies, demonstrating the efficacy of NK1 antagonists, especially
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`in the delayed phase of emesis [26,27]. These studies have con-
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`firmed that the triple combination of NK1 antagonist, 5—l—lT3
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`antagonist and dexamethasone seems to represent the best
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`treatment option.
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`In general, the NK1 receptor antagonists have been well-
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`tolerated. Adverse events occurring in > l0% of patients have
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`included dizziness, perversion of taste, headache, anorexia,
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`Gale, O'Neill & Humphrey
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`abdominal pain, constipation, diarrhoea and asthenia. Most
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`of these events have occurred at similar rates in patients
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`treated with NK1 antagonists and in those receiving the stand-
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`
`ard care of 5-HT3 antagonists plus dexamethasone. Diarrhoea
`
`
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`
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`appears more prevalent in the patient group treated with NK1
`antagonists, although diarrhoea is a common side effect in
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`patients treated with cisplatin. The overall benefit of the NK1
`antagonists in terms of improvements in patients’ quality of
`
`
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`
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`life is still to be determined.
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`Two Phase ll studies have also examined the efficacy of
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`NK1 receptor antagonists in post-operative nausea and vomit-
`
`ing (PONV). In a small study aimed at treatment of estab-
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`lished PONV following major gynaecological surgery,
`the
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`Glaxo NK1 antagonist, GR205l7l (vofopitant), was superior
`
`to placebo at controlling symptoms over a 24 h period follow-
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`
`
`ing iv. administration [28]. In a larger study looking at prophy-
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`laxis of PONV following abdominal hysterectomy, oral
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`dosing with the Pfizer NK1 antagonist, CP-l22,72l, was
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`superior to iv. treatment with a 5—HT3 antagonist [29]. In this
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`study, combination of the NK1 antagonist with a 5—HT3
`
`antagonist appears to prolong the emesis—free period and thus
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`be the most superior treatment option.
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`The only other form of emesis that has been studied clini-
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`cally with the NK1 receptor antagonists is that evoked by
`
`motion. In this small study in volunteers, GR205l7l, at a
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`close shown to be efficacious in the treatment of PONV, failed
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`to control motion—induced nausea either alone or in combina-
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`tion with a 5—HT3 receptor antagonist [30]. These data are in
`
`stark contrast to those obtained in motion—induced emesis in
`
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`animals, where NK1 antagonists were highly efficacious anti-
`
`emetic agents and raise the possibility that the broad spectrum
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`anti-emetic profile demonstrated in animals with this class of
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`agent may not be mirrored in humans.
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`3. Tachykinin NK1 receptor antagonists
`
`
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`
`
`Most major pharmaceutical companies are working towards
`
`
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`
`
`advancing improved new compounds to the clinic, as evi-
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`
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`
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`
`
`denced by the large number of patent applications published
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`
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`in recent years. For example, Astra Zeneca has expanded on a
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`previous claim with five new patent applications claiming
`
`
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`
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`novel naphthalenecarboxamides, such as compounds 1 — 6
`
`
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`
`
`
`[101]. The phenylsulphinyl naphthalenecarboxamides 1 ~ 3 are
`
`
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`
`
`relatively nonselective, binding to each of the tachykinin
`
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`
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`
`
`receptors, although with more affinity for NK1 and NK2 over
`
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`
`
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`NK3 [102-104]. The pharmacological properties of compound
`
`
`3, also known as ZDGOZI, have been studied extensively [31].
`
`
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`
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`
`
`Piperidinylbutyl naphthalene carboxamide derivatives such
`
`
`
`
`
`as the specifically claimed compound 4, reportedly provide
`
`
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`
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`
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`greater selectivity for NK1 and NK2 over NK3 [I05]. The substi-
`
`
`
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`tution pattern about the naphthalene and piperidine rings may
`
`
`
`
`
`
`
`
`
`also be altered to give compounds with enhanced selectivity for
`
`
`
`
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`
`
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`
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`
`
`
`
`
`
`either NK1 or NK2. However, the greatest NK1 selectivity is
`
`
`
`realised Via the aminobutyl— and the morpholinylbutyl—substi—
`
`
`
`
`
`
`tuted naphthamides (i.e., 5 and 6, respectively) [106]. The 3,4-
`
`
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`
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`
`Page3of11
`
`Expert Opin. Ther. Patents (2001) 11(] 2)
`
`
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`
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`1839
`
`
`
`Page 3 of 11
`
`

`
`Tachykinin NK, receptor antagonists for the control of chemotherapy-induced nausea and vomiting
`
`3 ZD6021
`
`
`
`0
`
`Cl
`
`ci
`
`° 0 ‘O
`'
`””“‘-“T O
`“W”?
`Q « .
`:1 I
`
`o
`
`Cl
`
`N
`
`/
`
`Cl
`
`5
`
`6
`
`dichloro substitution about the phenyl ring and the 3-cyano
`functionality of the naphthalene ring system appears to be par-
`ticularly important features in each of these series. Altogether
`these patents list over 120 synthesised examples and eight spe-
`cifically claimed compounds. Several examples are reported to
`be orally-active in guinea-pig models of extravasation and
`bronchoconstriction but no emesis data are reported.
`A 1998 report from Fujisawa [107] discusses structural mod-
`ifications of their previously patented [l08.l09] aroylpiperazine
`compounds. Several compounds were shown to be brain—pen-
`etrant and active at 1 mg/kg iv. in a copper sulfate-induced
`ferret emesis assay. This degree of potency is an improvement
`over the earlier patented compounds. The two patents list 196
`examples, 16 of which are specifically claimed and two of
`which (7 and 8) are shown.
`Claxo has reported a series of novel piperizine derivatives
`that feature an unusual urea central link between an aryl sub-
`stituted piperazine and Merck's bistrifluoromethyl phenethyl
`amine [I10]. Derivative 9 displays excellent oral activity in the
`CNS model of agonist-induced gerbil foot tapping (ED54) =
`0.04 mg/kg). The compound is formulated as the acetate salt
`and is suitable for ip. and sc. administration.
`
`The antl—emetic efficacy of NK1 receptor antagonists against
`chemotherapy-induced emesis is enhanced when combined with a
`
`5-l-i'i'3 receptor antagonist. For this reason, the efficacy of a
`combination of NK1 antagonist (GR205171 10) and the 5-
`I-IT3 antagonist. ondansetron, was
`assessed in motion-
`induced nausea [30]. Administration of CR205l7l with and
`without ondansetron was compared to placebo in a model of
`moderate motion-induced nausea. However. there were no
`significant differences between either GRZ05171 alone or
`GR205l7l plus ondansetron with placebo.
`Hoffmann—La Roche has reported recently four new sets
`of claims on carboxamide structures. including one each on
`pyridines [ill] and biphenyl derivatives [112] and two on pyri-
`midines [113.i1-1]. Together these patents list 245 synthetic
`examples and 88 specifically claimed compounds. The bulk
`of the claimed chemical matter lies in the pyrimidine series
`(compounds 11 and 12) and these compounds also appear to
`provide slightly greater in Vilro NK1 binding potencies. The
`pyrimidines each exhibit K, values of ~ 0.6 nM in CHO cells
`transfected with the human recombinant NKI
`receptor,
`while the pyridyl (13) and biphenyl (14) compounds exhib-
`ited potencies of 2.8 and 1.4 nM, respectively. In vivo bio-
`logical data were not provided. The Roche compounds are
`similar in structure to a series appearing in a Japanese patent
`issued to Yamanouchi. 15 Compounds are reported, includ-
`ing 15 and 15, but biological data are not supplied.
`
`1840
`
`Page 4 of 11
`
`Expert Opin. Ther. Patents (2001) 11[12)
`
`

`
`Gale, O'Neill & Humphrey
`
`N=N
`I
`HN\r
`
`F
`
`F
`
`F
`
`H
`\\N
`
`'4,/ Ox
`
`10GR205171
`
`F
`
`FF
`
`F
`
`FF
`
`N
`
`\ /
`
`N
`
`/
`
`O
`
`13
`
`F F
`
`
`
`16
`
`F
`
`
`
`Lilly has been issued a patent claiming bisindoles as tach-
`ykinin receptor antagonists and 5-HT receptor agonists [115].
`Although related somewhat to Lilly's Ianepitant, these struc-
`tures differ most notably in the presence of an additional
`lndole group, and thus giving it greater mass (l.e., com-
`pound IS). 60 Compound examples are named in the pat-
`ent but none are specifically claimed and experimental data
`are not reported.
`Merck has recently incorporated dialkylamine-substituted
`azo-heterocycles on their previously reported morpholine
`template via a methylene bridge to the ring nitrogen. These
`compounds offer increased aqueous solubility and long dura-
`tion of action. This obviates the need for a prodrug as in the
`case of MK-869 (19). A specific crystalline polymorph of
`compound 20 that is thermodynamically stable and which is
`suitable for inclusion in a pharmaceutical formulation has
`been claimed [116] and two chemical process patents to this
`compound have also been granted |l17,118]. A specific thermo-
`dynamically stable polymorph of MK-869 (L-754,030) was
`also claimed as suitable for inclusion in pharmaceutical for-
`mulations [H9]. A further report describing the anti—emetic
`
`profile of MK-869 and its water soluble prodrug L—758,298
`demonstrated efficacy against acute and delayed cisplatin-
`induced emesis in ferret |23.l20l.
`Several specific therapeutic patent applications have been filed
`for morpholine 21 [121-124] in addition to the claims of the origi-
`nal report [125]. The hydroxymethyl benzyl substltuent lrnproves
`physical chemical properties such as solubility in the same man-
`ner as azo-heterocycles compared with MK-869. Compound 21
`displays the following preclinical profile: NKI [C50 = 0.12 nM;
`antagonism of substance P-induced gerbil foot tapping: IC50 =
`0.38 mg/kg (5 min). 2.2 mg/kg (24 h); inhibition of substance P-
`induced emesis in the ferret: IDQO lmg/kg po; inhibition of sub-
`stance P-induced guinea-pig vocalimtioni [D50 0.9lmg/kg p.o. A
`variety of non-basic substituted pyran NK1 antagonists have also
`been reported with binding affinity (IC50) reported S 100 nM
`1120]. The pyran substituents range from the aminomethyltriazole
`of 22 to hydroxymethyl, carboxy and vinyl.
`A series of splro-piperidine derivatives with and without
`direct phenylpiperidine substitution has been reported
`(compounds 23 and 24, respectively)
`[127.l28]. The trifluor-
`omethyltetrazole originally favoured by Glaxo has been incor-
`
`Expert Opln. Then Pazents(2001) 11(12)
`
`1841
`
`Page 5 of 11
`
`

`
`Tachykinin NK. receptor antagonists for the control of chemotherapy-induced nausea and vomiting
`
`H
`
`3 o
`| "W
`O
`
`.
`:
`NH
`
`'
`
`HN \
`
`\o
`
`N
`H
`
`F\
`
`F
`F
`
`’I,,'
`
`F
`
`F
`
`18
`
`HN
`
`0 \
`
`F
`
`F
`F
`
`(EH
`’I.,
`
`‘.\O
`
`j"I,
`
`F
`
`F F
`
`N
`
`N/ \
`\\
`
`F
`
`O
`
`19 MK-869
`
`/"‘\
`
`20
`
`porated into each system. Both series reportedly display NK,
`binding affinity < 1 },LM and attenuate substance P-induced
`retching in ferret. It should be noted that the aromatic ring
`appended to the furan ring may be a heterocycle [129] or may
`be substituted by imidazole or fluoromethoxy to reduce meta-
`bolic degradation 1130]. Replacement of the furan ring with a
`pentanone affords a third series of spirocyclic piperidine
`antagonists, represented by 25. with and without substitution
`of the piperidine nitrogen 1131]. The 23 compounds specified
`have binding affinity < 100 nM. Merck has also revealed non-
`basic spiro-ethercycloalkane structures 26 as NKI antagonists,
`although the scope of the claims also includes basic com-
`pounds [132.I33|. The reported binding affinities span a range
`from 0.5 nM to 10 i1M.
`Merck has reported a Z-arylindole lead 27 from a combina-
`torial
`library [134] and biological data has been published
`[32.33]. These reports describe the SAR information designed
`to improve pharmacodynamics, which lead to 28 as one of
`several potent antagonists in the substance P-induced gerbil
`foot tapping assay. The authors indicate that high first pass
`metabolism limited bioavailability of these compounds. The
`structurally-related 4.4-disubstituted piperidine
`29 was
`claimed as a combined SSRI/NK, antagonist [I35]. This class
`of compounds
`reportedly exhibit NK1 binding affinity
`< 10nM and attenuate substance P-induced retching in ferret.
`
`21
`
`22
`
`Novartis has continued their work in the area of proline
`dipeptides exemplified by the earlier lead compound 30. The
`present series includes the quinazoline 31, which is designated
`the preferred agent [I36]. These compounds span a range of K,
`values from 0.01 - 10 nM at the NKI receptor as measured by
`PH]-substance P displacement from Cos-7 cells transfected
`with the human recombinant NK] receptor. The current
`application also covers compounds wherein a quinazoline
`nitrogen atom is replaced with oxygen or sulfur. Seven syn-
`thetic examples are provided but no specific biological data
`are given.
`Pfizer has continued to discuss novel antagonists within
`their amino-piperidine domain. The most recent report [137]
`stems from incorporation of a fused tricyclic ring containing
`an embedded tetrazole (compound 32). These structures
`extend the scope of previous reports from Pfizer [I38] and from
`G1axoWellcome [I39-141]. The agents display antagonism of
`substance P-induced gerbil
`foot
`tapping and capsaicin-
`induced plasma extravasation. These compounds have been
`profiled against verapamil Ca2* binding In rat heart and meta-
`bolic half-life in human liver microsomes. In a related discus-
`
`sion. a claim from I-lisamitsu has appeared for compounds of
`general Type 33 I142]. Compounds from this series exhibit
`NK1 binding in the range of 1 nM and are 90% efficacious at
`0.3 mg/kg in an in Viva model of cisplatin-induced emesis.
`
`1842
`
`Page 6 of 11
`
`Expert Opin. Ther. Patents (2001) 11(12)
`
`mm
`
`17 LY303870
`(Lanepitant
`
`O”
`
`F
`
`F
`F
`
`r F
`
`r
`
`’/.5
`‘\\ 0
`
`"I.
`
`F
`
`O
`
`F F
`O
`O
`[NJ-‘I’
`/Nfi) \ N/N\
`
`"
`
`\\N
`
`NH
`
`E
`
`an
`
`Njl’ll
`
`F
`
`F F
`
`O
`
`[N
`F N\')
`
`/\
`
`N
`
`\§/NH
`
`

`
`Gale, O'Neill & Hunphrey
`
`
`
`34(R=H)
`
`35 R=
`
`Wamer-Lambert (now Pfizer Global R&D) had previously
`discussed a tryptophan-based NK1 antagonist found to be
`efficacious in the ferret emesis model (34) I143]. They have
`now extended the scope of this class of compound to include
`water-soluble prodrugs such as the compound 35 I144]. Intra-
`venous dosing of cannulated rats with 36 demonstrated 100%
`reconversion to the parent antagonist as demonstrated by
`HPLC analysis of plasma samples. This prodrug also achieved
`46% bioavailability upon p.o. administration.
`
`Sanofi has expanded on their previous claims by incorpo-
`rating piperidine or morpholine rings into the earlier struc-
`tures to yield 36 - 38 [145-147]. The resultant rigidification of
`the structures appears to have imparted greater selectivity for
`the NK1 receptor. The compounds reportedly exhibit NK1
`receptor binding affinities of ~ 0.01 nM whereas the NK2 and
`NK3 affinities are ~ 10 and 100 nM. respectively. However,
`no specific data are provided.
`
`Expert Opin. Ther. Patents (2001) 11(12)
`
`1843
`
`Page 7 of 11
`
`

`
`Tachykinin NK, receptor antagonists for the control of chemotherapy-induced nausea and vomiting
`
`N
`
`I / CI
`
`Cl
`
`C
`
`Cl
`
`N
`
`I
`
`0
`
`37
`
`0
`
`38
`
`0
`
`Cl
`
`40
`
`Cl
`
`CI
`
`Cl
`
`H0
`
`\N
`|
`
`I
`N
`
`0
`
`Cl
`
`41
`
`CI
`
`Schering has claimed the use of piperazine derivatives as
`selective antagonists of either NKI, NK2. or NK3_ as well as
`for use as NKl/NK2 dual receptor antagonists [I48]. 52 Com-
`pound examples are described. with 38 being specifically
`claimed. The piperazine 39 appears to be the highest affinity
`NK1 antagonist with a Kivalue of 3 nM. The compound also
`has affinity for the NK2 receptor (K, = 25 nM). Interestingly,
`replacement of one of the piperazine rings of this compound
`with a plperidlne ring reverses the selectivity, providing a
`compound that is more selective for the NK2 receptor over the
`NKI receptor (compound 40, 7.5 and 71 nM. respectively).
`A 1997 Schering patent claims substituted oximes, hydra-
`zones and olefins as tachykinin receptor antagonists [149]. The
`oxime series was subsequently found to be more potent than
`the hydrazones and oleflns. prompting publication of addi-
`tional patent documents covering these structures (e.g., 41 -
`43]
`[150.l51]. Together,
`these documents report 187 synthe-
`sised examples.
`including 162 specifically claimed com-
`pounds. The compounds were essentially non-selective,
`displaying comparable affinity for NK] and NK2 receptors
`(~ 0.2 - 6 nM). Some of the compounds are also high affinity
`
`NK3 antagonists (K, ~ 0.05 - 50 nM) although these struc-
`tures are not specifically identified. The binding assays were
`performed on CHO cells transfected with human recom-
`binant receptors and provided K, values of ~ 0.2 v 6 nM. The
`dual NK1/NKZ activities make the compounds attractive as
`potential asthma treatments (NKI and NK2 receptors are
`associated with vascular leakage and with muscle contraction,
`respectively) and this appears to be the main focus of the pat-
`ents. Emesis is claimed as an additional potential therapeutic
`indication, but no data are included to support this.
`Recent reports from Takeda describe napthiridine deriva-
`tives such as 44 - 46 that includes the clinical candidate TAK-
`
`637 [34.35.152]. The 8-membered azacyclic ring was originally
`installed to simplify synthetic and developmental issues aris-
`ing from atropisomerism of the earlier straight chain amide
`series. The chiral 9-methyl group was likewise installed for
`synthetic reasons. enabling a stereoselective synthesis of the
`desired atropisomer. It was subsequently found that that the
`newer series, although less potent in vitro, exhibited higher
`in viva potencies and were orally-active in a guinea-pig model
`of capsaicin-induced plasma extravasation. Replacement of
`
`1844
`
`Page 8 of 1