REVIEW
`
`www.rsc.org/npr | Natural Product Reports
`
`Natural products to drugs: natural product-derived compounds in
`clinical trials
`
`Mark S. Butler*ab
`
`Received 20th March 2008
`First published as an Advance Article on the web 7th May 2008
`DOI: 10.1039/b514294f
`
`Covering: 2005 to 2007
`
`Natural product and natural product-derived compounds that are being evaluated in clinical trials or
`are in registration (as at 31st December 2007) have been reviewed, as well as natural product-derived
`compounds for which clinical trials have been halted or discontinued since 2005. Also discussed are
`natural product-derived drugs launched since 2005, new natural product templates and late-stage
`development candidates.
`
`1
`2
`3
`
`in infectious
`
`Introduction
`NP-derived drugs approved from 2005 to 2007
`Compounds undergoing evaluation in infectious
`diseases
`3.1 Antibacterial
`3.2 Antifungal
`3.3 Antiparasitic
`3.4 Antiviral
`3.5 Halted or discontinued compounds
`diseases
`Neurological disease
`4
`4.1 Compounds undergoing evaluation in neurological
`diseases
`4.2 Halted or discontinued compounds in neurological
`diseases
`Cardiovascular and metabolic disease
`5
`5.1 Compounds undergoing evaluation in cardiovascular
`and metabolic diseases
`5.2 Halted or discontinued compounds in cardiovascular
`and metabolic diseases
`Immunological, inflammatory and related disease
`6
`6.1 Compounds undergoing evaluation in immunological,
`inflammatory and related diseases
`6.2 Halted or discontinued compounds in immunological,
`inflammatory and related diseases
`Oncological disease
`7
`7.1 Small-molecule anticancer agents
`7.2 NP-antibody anticancer conjugates
`8
`New natural product templates
`9
`Conclusions
`10 Acknowledgements
`11 References
`
`aMerLion Pharmaceuticals, 1 Science Park Road, The Capricorn #05-01,
`Singapore Science Park II, Singapore 117528. E-mail: mark@
`merlionpharma.com; Fax: +65 6829 5601; Tel: +65 6829 5611
`bDepartment of Chemistry, National University of Singapore, 3 Science
`Drive 3, Singapore 117543
`
`1
`
`Introduction
`
`This review describes natural products (NPs), semi-synthetic NPs
`and NP-derived compounds that are undergoing clinical evalu-
`ation or registration at the end of December 2007 by disease area
`and follows a similar format to the previous review in this series.1
`NP-derived drugs launched since 2005 are discussed in Section 2,
`while compounds undergoing clinical evaluation or compounds
`that have been halted or discontinued since 2005 are listed by
`disease area: Infectious disease (Section 3), Neurological disease
`(Section 4), Cardiovascular and metabolic disease (Section 5),
`Immunological, inflammatory and related diseases (Section 6)
`and Oncology (Section 7). Clinical candidates with new struc-
`tural templates are discussed in Section 8, while late-stage
`development compounds are summarised in Section 9.
`Compounds are classified into 3 groups: NPs, semi-synthetic
`NPs or NP-derived. NPs are classified as a NP in this review even
`if they are produced synthetically for clinical studies or for the
`market. Semi-synthetic NPs are compounds that were derived
`from a NP template using semi-synthesis, while NP-derived
`compounds are synthetically derived or in some cases inspired
`from a NP template. These definitions are simpler compared to
`those used in Newman, Cragg and Snader’s reviews2,3 and
`Newman and Cragg’s 2007 update.4 No number has been
`assigned to a compound if it does not have a publicly disclosed
`structure. Compounds derived from primary metabolites (e.g.
`steroids, nucleosides, prostaglandins, sialic acid5 and tyrosine),
`vitamins (e.g. vitamin D and retinoids6), hormones and protein
`fragments, herbal mixtures,7,8 polyamines,9,10 porphyrin11 deriv-
`atives and new uses of existing drugs have not been listed
`exhaustively. In addition,
`the background description for
`compounds in this review that were also discussed in the previous
`review1 may not be as detailed.
`A brief description of terms used during the drug approval
`process: an Investigational New Drug Application (IND) (or
`equivalent elsewhere in the world) must be made to the United
`States of America (US) Food and Drug Administration (FDA),
`European Medicines Agency (EMEA) or equivalent agency
`before clinical trials can commence. Once clinical trials have
`been completed successfully, the applicant files a New Drug
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Nat. Prod. Rep., 2008, 25, 475–516 | 475
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
` / Journal Homepage
`
` / Table of Contents for this issue
`
`AVENTIS EXHIBIT 2103
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Table 1 NP-derived drugs launched since 2005 by year with reference to their lead compound, classification and therapeutic area23–28,a
`
`Year
`
`Generic name (trade name)
`
`Lead compound
`
`Classification
`
`Disease area
`
`2005
`2005
`2005
`2005
`2005
`2005
`2006
`2006
`2007
`2007
`2007
`2007
`2007
`
`dronabinol 1/cannabidol 2 (SativexÒ)
`fumagillin 3 (FlisintÒ)
`doripenem 4 (FinibaxÒ/DoribaxÔ)
`tigecycline 6 (TygacilÒ)
`ziconotide 8 (PrialtÒ)
`zotarolimus 9 (EndeavorÔ stent)
`anidulafungin 11 (EraxisÔ/EcaltaÔ)
`exenatide 13 (ByettaÔ)
`lisdexamfetamine 14 (VyvanseÔ)
`retapamulin 16 (AltabaxÔ/AltargoÔ)
`temsirolimus 18 (ToriselÔ)
`trabectedin 19 (YondelisÔ)
`ixabepilone 20 (IxempraÔ)
`
`dronabinol 1/cannabidol 2
`fumagillin 3
`thienamycin 5
`tetracycline 7
`ziconotide 8
`sirolimus 10
`echinocandin B 12
`exenatide-4 13
`amphetamine 15
`pleuromutilin 17
`sirolimus 10
`trabectedin 19
`epothilone B 21
`
`NPs
`NP
`NP-derivedb
`semi-synthetic NP
`NPb
`semi-synthetic NP
`semi-synthetic NP
`NPb
`NP-derivedb
`semi-synthetic NP
`semi-synthetic NP
`NPc
`semi-synthetic NP
`
`pain
`antiparasitic
`antibacterial
`antibacterial
`pain
`cardiovascular surgery
`antifungal
`diabetes
`ADHD
`antibacterial (topical)
`oncology
`oncology
`oncology
`
`a In October 2006, Merck gained FDA approval for the use of vorinostat (ZolinzaÔ, suberoylanilide hydroxamic acid, SAHA) 22 for the treatment of
`advanced, refractory cutaneous T-cell lymphoma. In the previous review in this series,1 vorinostat 22 was classified as ‘‘NP-derived’’ due to its chemical
`and biological similarity to trichostatin 23,30 an actinomycete-derived HDAC inhibitor.31,32 However, Marks and Breslow have since published
`a review33 indicating that vorinostat 22 was developed independently of trichostatin 23 but later recognition of their structural similarities helped
`elucidate the mechanism of action of 22.34 b These drugs are manufactured by total synthesis. c Trabectedin is produced semi-synthetically from
`cyanosafracin B 24.35
`
`Application (NDA) with the FDA or a Marketing Authorization
`Application (MAA) with the EMEA to seek the drug’s approval
`for marketing in the US and Europe respectively. The agency will
`then reply with an ‘‘approval letter’’, ‘‘non-approval letter’’ or
`‘‘approvable letter’’. An ‘‘approval letter’’ allows the applicant to
`begin marketing the product, while a ‘‘non-approval
`letter’’
`rejects the application. An ‘‘approvable letter’’
`informs the
`applicants that the agency have completed their scientific review
`and determined that the application can be approved pending
`resolution of minor deficiencies identified in the letter or during
`an inspection of the manufacturing facilities.
`Kinghorn and co-workers published a related review ‘‘Drug
`discovery from natural sources’’ in 2006, which lists NP and NP-
`derived drugs in clinical trials and on the market.12 Also of
`general interest are the 2005 reviews ‘‘The search for novel drug
`leads for predominately antitumor therapies by utilizing mother
`nature’s pharmacophoric libraries’’,13 ‘‘The evolving role of
`natural products in drug discovery’’,14 ‘‘The renaissance of
`natural products as drug candidates’,15 and ‘‘Natural products as
`drug leads: an old process or the new hope for drug discovery?’’,16
`the 2006 reviews ‘‘Drug discovery from natural products’’,17
`
`‘‘Small molecule natural products in the discovery of therapeutic
`agents: the synthesis connection’’,18 and ‘‘The role of pharma-
`cognosy in modern medicine and pharmacy’’,19 and finally the
`2007 reviews
`‘‘New aspects of natural products in drug
`discovery’’,20 ‘‘The value of natural products to future pharma-
`ceutical discovery’’,21 and ‘‘Natural products as a screening
`resource’’.22 Reviews that are specific to the therapeutic area are
`listed in the appropriate sections.
`Although this review represents a thorough evaluation of
`publicly available data,
`there may be some NP-derived
`compounds that have been excluded. The status of compounds
`undergoing clinical investigation and the companies involved can
`change rapidly and readers are encouraged to consult the recent
`literature, company web pages and clinical trial registers such as
`the US National Institutes of Health’s (NIH) website (http://
`www.clinicaltrials.gov) for the latest information.
`
`2 NP-derived drugs approved from 2005 to 2007
`
`A total of 13 NP and NP-derived drugs were approved for
`marketing worldwide (Table 1) from 2005 to 2007 (see ref. 1 for
`
`Mark Butler received a PhD from The University of Melbourne for his research on novel metabolites
`from Southern Australian marine sponges in 1992. After postdoctoral work with Prof. Pettit at the
`Arizona State University, he joined the newly established Queensland Pharmaceutical Research Institute
`(now part of the Eskitis Institute for Cell and Molecular Therapies), a joint venture between Griffith
`University and AstraZeneca. In 1999, he moved to Singapore to lead the Natural Product Chemistry
`group at the Centre of Natural Product Research (CNPR), which was part of the Institute of Molecular
`and Cell Biology and affiliated with GlaxoSmithKline. In 2002, CNPR privatized to become MerLion
`Pharmaceuticals where his present position is Director of Natural Product Chemistry. He has over 40
`papers on various aspects of natural product chemistry and in 2002 was awarded the Matt Suffness
`(Young Investigator) Award by the American Society of Pharmacognosy. Since 2006, he has been an
`Adjunct Associate Professor in the Department of Chemistry at the National University of Singapore.
`
`Mark Butler
`
`476 | Nat. Prod. Rep., 2008, 25, 475–516
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
`

`
`a similar table from 1998 to 2004), with 5 being classified as NPs, 6
`semi-synthetic NPs and 2 NP-derived drugs. In addition,
`ziconotide 8, exenatide 13, retapamulin 16, trabectedin 19 and
`ixabepilone 20 are the first members of new human drug classes.
`To further support the importance of NPs in drug discovery, it
`should be noted that 6 of 27 small molecule drug launches in 2005
`(22%), 2 of 21 in 2006 (9%) and 5 of 21 (24%) in 2007 were NPs or
`derived from NPs,23–28 and the numbers are greater if you consider
`drugs inspired from other naturally occurring molecules such as
`steroids, nucleosides, prostaglandins, hormones and vitamins.
`Lisdexamfetamine 14 was classed as NP-derived due to the
`structural relationship between amphetamine 15 and ephedrine.29
`SativexÒ (GW Pharmaceuticals) is a mixture of the cannabi-
`noids, dronabinol (D9-THC) 1 and cannabidol 2, which was first
`launched in Canada in April 2005 as an adjunctive treatment for
`the symptomatic relief of neuropathic pain in multiple sclerosis
`(MS) patients.36–38
`In August 2007, Health Canada also
`approved SativexÒ as adjunctive analgesic for patients with
`advanced cancer who experience moderate to severe pain with
`the highest tolerated dose of strong opioid therapy. SativexÒ is
`undergoing a Phase II/III cancer pain trial in the US and late-
`stage clinical development in Europe, but is already prescribed in
`the UK on a named patient basis for both pain indications.39
`In September 2005, fumagillin (FlisintÒ, Sanofi-Aventis) 3 was
`approved for use in the treatment of intestinal microsporidiosis
`in France. Microsporidiosis is a disease caused by the spore-
`forming unicellular parasite Enterocytozoon bieneusi, which is of
`major concern to immunocompromised patients as it can cause
`chronic diarrhoea.40,41 Fumagillin 3 was first isolated in 1949
`from Aspergillus fumigatus and used shortly thereafter to treat
`intestinal amoebiasis.42,43 In addition, semi-synthetic derivatives
`of fumagillin 3 with antiangiogenic activity have undergone
`clinical evaluation for the treatment of cancer (Section 7.2).
`
`FDA review, while in Europe treatment of HAP and complicated
`urinary tract infections are under review. Other carbapenems
`undergoing clinical evaluation are described in Section 3.1.
`
`Tigecycline (TygacilÒ) 6 is the first member of a new generation
`of tetracyclines 7 called glycylcyclines that was developed by
`Wyeth to have more potent antibacterial activity and reduced
`bacterial efflux.49–51 Tigecycline 6 was approved by the FDA in
`June 2005 for use in the treatment of complicated skin and skin
`structure infections (cSSSIs) and complicated intra-abdominal
`infections. In addition, a supplemental NDA was submitted to
`the FDA in October 2007 for the treatment of patients with
`community-acquired pneumonia (CAP). Tigecycline 6 was
`approved for use in Europe in May 2006 for cSSSIs and
`complicated intra-abdominal infections.
`Ziconotide (PrialtÔ) 8 is a synthetic version of the N-type
`calcium channel blocker u-conotoxin MVIIA, a peptide first
`isolated from the venom of Conus magus.52 Ziconotide 8 was
`launched by Elan in both the US and Europe in 2005 for the
`treatment of patients suffering from chronic pain.53 In March
`2006, Eisai obtained the rights to market PrialtÔ in Europe.
`Further information on conotoxin-derived development candi-
`dates can be found in Section 4.
`
`Doripenem (FinibaxÒ, DoribaxÔ) 4 is a synthetic carbape-
`nem-type b-lactam that was launched in 2005 in Japan by
`Shionogi & Co. as a broad-spectrum antibiotic.44–46 The first
`carbapenem to be identified was the actinomycete-derived NP
`thienamycin 5.47,48 Johnson & Johnson (J&J) (formerly Peninsula
`Pharmaceuticals) obtained formal FDA approval in October
`2007 for use of doripenem 4 in the treatment of complicated
`intra-abdominal and complicated urinary tract
`infections,
`including pyelonephritis. The use of doripenem 4 for treatment
`of hospital-acquired (nosocomial) pneumonia (HAP) is under
`
`In July 2005, Medtronic received European approval for the
`sale of the EndeavorÔ drug-eluting coronary stent that consists
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Nat. Prod. Rep., 2008, 25, 475–516 | 477
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
`

`
`of a cobalt-based alloy integrated with a biomimetic phosphor-
`ylcholine polymer.54–56 EndeavorÔ delivers the active principle
`zotarolimus (ABT-578) 9,57 a semi-synthetic derivative of siroli-
`mus (rapamycin) 10,
`into surrounding vascular structures,
`inhibiting cell proliferation, preventing scar tissue formation and
`minimizing restenosis in angioplasty patients. Sirolimus 10 was
`first isolated from a soil sample of Streptomyces hygroscopicus58
`and is marketed as an immunosuppressant by Wyeth under the
`trade name RapamuneÒ. The EndeavorÔ stent is currently used
`in more than 100 countries worldwide and is moving closer to US
`registration after a positive recommendation by an FDA
`Advisory Committee in October 2007.
`Pfizer obtained FDA approval in February 2006 (EraxisÔ in
`the US) and EMEA approval in July 2007 (EcaltaÔ in Europe)
`for the use of anidulafungin 11 in the treatment of invasive and
`oesophageal candidiasis and candidemia.59,60 Anidulafungin 11 is
`a semi-synthetic derivative of the fungal metabolite echinocandin
`B 12 originally developed by Eli Lilly61 and licensed to Vicuron
`Pharmaceuticals, who were purchased by Pfizer in June 2005.
`Further information on echinocandin antifungal drugs can be
`found in Section 3.
`Eli Lilly and Amylin Pharmaceuticals obtained FDA and
`EMEA approval in April 2005 and November 2006 respectively
`for the use of exenatide (ByettaÔ) 13 as an adjunctive therapy to
`improve blood sugar control in patients with type 2 diabetes.62,63
`Exenatide 13, originally named exenatide-4, is a 39 amino acid
`peptide isolated from the oral secretions of the Gila monster
`(Heloderma suspectum), a poisonous lizard found in the south-
`western US and northern Mexico.64,65 Exenatide 13 has a struc-
`ture similar to glucagon-like peptide-1 (GLP-1), a human
`hormone that helps the pancreas to regulate glucose-induced
`insulin secretion when the blood glucose levels are elevated, and
`is the first compound in a new class of drugs called ‘‘incretin
`
`mimetics’’. Other incretin mimetics in clinical evaluation are not
`described in this review but further information can be obtained
`in these references.62,66–68
`Although the underlying causes of Attention-Deficit Hyper-
`activity Disorder (ADHD) are not well understood, there is
`evidence suggesting that dopaminergic and noradrenergic
`neurotransmission are dysregulated in ADHD. Methylphenidate
`and amphetamines have been used to treat ADHD for many
`years but these drugs are controlled substances due to their abuse
`potential.69 New River Pharmaceuticals designed an amphet-
`lisdexamfetamine (VyvanseÔ, NRP104) 14,
`amine prodrug,
`which is converted to D-amphetamine 15 in the gastrointestinal
`tract after oral administration and, as a consequence, has
`reduced abuse potential.69–71 In February 2007, New River and
`Shire Pharmaceuticals obtained FDA approval for the use of
`lisdexamfetamine 14 to help treat ADHD, and in April 2007
`Shire bought New River.
`Retapamulin (SB-275833) 16 is a semi-synthetic derivative of
`the fungal metabolite pleuromutilin 17, which exerts its antimi-
`crobial activity by binding to the 50S bacterial ribosome.72–74 A
`1% retapamulin ointment (called AltabaxÔ in the US and
`AltargoÔ in Europe) developed by GlaxoSmithKline (GSK) was
`approved by the FDA in April 2007 and the EMEA in June 2007
`for the topical treatment of impetigo caused by Staphylococcus
`aureus or Streptococcus pyogenes.75–77 Further information on
`other pleuromutilin derivatives undergoing clinical evaluation
`can be found in Section 3.
`Temsirolimus (ToriselÔ, CCI-779) 18 is a semi-synthetic
`derivative of sirolimus 10 that was approved in the US in May
`2007 and Europe in November 2007 for the treatment of advanced
`renal cell carcinoma.78–81 Temsirolimus 18 is the first mTOR
`inhibitor approved for use in oncology, and other semi-synthetic
`sirolimus 10 derivatives are discussed in Sections 6 and 7.
`
`478 | Nat. Prod. Rep., 2008, 25, 475–516
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
`

`
`Trabectedin (YondelisÔ, ecteinascidin-743, ET-743) 19, a
`tetrahydroisoquinoline alkaloid produced by the ascidian
`Ecteinascidia turbinata,82–84 was approved by the EMEA in
`September 2007 for the treatment of advanced soft tissue
`sarcoma.85,86 Trabectedin 19 is in Phase III clinical trials for the
`treatment of ovarian cancer (with J&J in the US) and other
`ongoing Phase II trials include paediatric sarcomas, breast and
`prostate cancers. Trabectedin 19 binds to the minor groove of
`DNA and disrupts the cell cycle, causing cell proliferation
`inhibition, and is produced commercially semi-synthetically from
`the eubacterium-derived cyanosafracin B 24.35
`Ixabepilone (IxempraÔ, BMS-247550) 20 is a semi-synthetic
`derivative of epothilone B 21 developed by Bristol-Myers Squibb
`(BMS) that was approved in October 2007 by the FDA for the
`treatment of breast cancer, either as a monotherapy or in
`combination with capecitabine.87–90 Ixabepilone 20, like other
`epothilones, binds directly to b-tubulin subunits on microtu-
`bules, leading to suppression of microtubule dynamics, blocking
`of cells in the mitotic phase and ultimately leading to cell death.
`The status of other epothilone derivatives in clinical evaluation is
`discussed in Section 7.
`Finally, it is worth noting that VeregenÔ (PolyphenonÒ E
`ointment), a defined mixture of catechins extracted from green
`tea leaves,91–93 became the first herbal medicine to receive FDA
`approval in 2006. VeregenÔ was developed by MediGene AG
`and launched in the US by Bradley Pharmaceuticals in December
`2007 for the treatment of genital warts.94
`
`3 Compounds undergoing evaluation in infectious
`diseases
`
`3.1 Antibacterial
`
`As with immunosuppression and to a lesser extent oncology,
`NP-derived drugs have played a pivotal role in anti-infective
`drug development.48,95–99 With the notable exception of quino-
`lones, the majority of antibacterial drugs currently in clinical use
`are NPs or were designed using NP templates. The ability of an
`organism to produce effective antibacterial compounds gives it
`an evolutionary advantage over other organisms and it is not
`surprising that many different NPs have evolved to interact with
`specific antibiotic protein targets. Also, the intrinsic ability of
`NP-derived drugs to penetrate bacterial cell membranes despite
`
`often having complex structures is a desirable and often
`privileged property.100 Worries about shrinking development
`pipelines, economics, clinical trial design and eventual resistance
`has placed increasing pressure on antibacterial research. This,
`coupled with the increased difficulty identifying of new druggable
`templates, especially with novel mechanisms of action, has made
`many pharmaceutical companies reduce or completely cease
`their antimicrobial research and development efforts. Nowhere is
`this situation better demonstrated than Payne and co-workers
`review describing GSK’s limited success using a genomics-based
`platform for antibacterial drug discovery.101 Despite the diffi-
`culties,101–107 there still are a significant number of NP-derived
`antibacterial compounds undergoing clinical evaluations but
`most are based on well known antibacterial templates.108,109
`b-Lactams inhibit the formation of peptidoglycan cross links
`in the bacterial cell wall, leading to bacterial death, and have
`been the mainstay for treating community-acquired infections
`since the commercialization of penicillins in the 1940s. There are
`presently 9 b-lactams (2 cephalosporins, 6 carbapenems and 1
`penem) in clinical trials or undergoing drug registration.110,111 As
`discussed in Section 2,
`the carbapenem doripenem 4 was
`launched in Japan in 2005 and obtained FDA approval
`in
`October 2007. In addition to these compounds, Gilead are
`evaluating an inhaled lysine salt formulation of the monobactam
`aztreonam (CaystonÔ) 25 in Phase III clinical trials as a treat-
`ment for cystic fibrosis sufferers who have a pulmonary infection
`of the Gram-negative bacteria Pseudomonas aeruginosa.112,113
`Aztreonam 25 is an existing intravenous (IV) antibiotic first
`launched in 1984.
`Ceftobiprole medocaril (BAL-5788) 26 is a fourth-generation
`cephalosporin that has potent bactericidal activity against
`methicillin-resistant Staphylococcus aureus (MRSA) and peni-
`cillin-resistant Streptococcus pneumoniae (PRSP).114–116 Basilea
`Pharmaceutica and the J&J affiliate Cilag GmbH International
`filed an MAA on 18 June 2007 and an NDA on 21 May 2007 for
`the treatment of cSSSIs. In March 2008, Basilea received an
`Approvable Letter indicating that 26 was approvable subject to
`completion and assessment of clinical study site inspections,
`assessment of clinical and microbiological data provided but not
`yet reviewed, and further characterization of patients with
`diabetic foot infections. In addition, various Phase III trials are
`underway for hospital- and community-acquired pneumonia
`(HAP/CAP). Ceftaroline acetate (PPI-0903, TAK-599) 27, which
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Nat. Prod. Rep., 2008, 25, 475–516 | 479
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
`

`
`is being evaluated by
`originally was discovered by Takeda,
`Forest Laboratories in Phase II trials for the treatment of cSSSi
`and CAP.117–120
`tebipenem pivoxil
`The most advanced carbapenem is
`(ME-1211, L-084) 28, which is being evaluated in Phase III trials
`in Japan by Meiji Seika as a broad-spectrum antibiotic.121–123
`Tomopenem (CS-023, RO4908463, R1558, Daiichi Sankyo)
`29124–126 and PZ601 (SM-216601, Protez,
`licensed from
`Dainippon Sumitomo) 30127,128 are in Phase II trials, while
`ME-1036 (CP5609) (Forest and Meiji Seika) 31, is in Phase I
`evaluation.129,130 Pfizer are evaluating a carbapenem, sulopenem
`(CP-70429) 32, and a prodrug, PF-3709270, in Phase I trials.131–133
`It is interesting to note that sulopenem 32 was first developed in
`the 1980s but clinical development was never completed despite
`32 being well tolerated.
`Faropenem daloxate (SUN-208, BAY-56-6824) 33 is an orally
`active, penem-type b-lactam that was licensed to Replidyne by
`Daiichi Suntory Pharma.134–136 Faropenem daloxate 33 is a
`pro-drug of faropenem, an antibiotic which has been used in
`Japan since 1997. Replidyne submitted an NDA to the FDA in
`December 2005 for treatment of acute bacterial sinusitis (ABS),
`acute exacerbation of chronic bronchitis (AECB), CAP and
`uncomplicated skin and skin structure infections
`(uSSSi).
`Although Replidyne’s NDA was accepted by the FDA, an
`internal FDA panel for AECB subsequently indicated that
`
`non-inferiority trials were no longer appropriate for approval in
`AECB, and another Phase III clinical trial had to be initiated using
`a superiority design. In October 2006, the FDA issued a Non-
`Approvable Letter for faropenem daloxate 33 calling for further
`superiority-designed clinical trials. In March 2007, Replidyne
`announced that the FDA had agreed to Phase III clinical devel-
`opment programmes consisting of one placebo-controlled trial in
`each of ABS and AECB and two non-inferiority trials in CAP.
`These additional trials have certainly delayed the launch of
`faropenem daloxate 33, and we may never see the drug marketed.
`Also, the changing from placebo-based to superiority-based trials
`during Phase III evaluation has caused considerable debate.
`There are 3 semi-synthetic glycopeptides,137,138 dalbavancin 34,
`telavancin 35 and oritavancin 36, in late-stage clinical develop-
`ment. In addition, a vancomycin–cephalosporin heterodimer,
`TD-1792 37, is discussed later in this section. Vancomycin 38 and
`related glycopeptides are isolated from various actinomycetes
`and inhibit bacterial growth through binding to the D-Ala-D-Ala
`termini of bacterial peptidoglycan precursors, which prevents the
`transglycosylation and transpeptidation reactions essential for
`cell wall production. Dalbavancin (ZevenÒ, BI-397) 34 is a
`semi-synthetic derivative of the teicoplanin analogue A40926
`39, discovered by Biosearch Italia and being developed by
`Pfizer.139–142 Vicuron (now part of Pfizer) filed an NDA for the
`treatment of cSSSi in February 2005 and since then 2 Approvable
`
`480 | Nat. Prod. Rep., 2008, 25, 475–516
`
`This journal is ª The Royal Society of Chemistry 2008
`
`Published on 07 May 2008. Downloaded by INFOTRIEVE on 25/03/2015 12:27:20.
`
`View Article Online
`
`

`
`Letters delaying approval have been received.143 The first Letter
`in June 2006 focused on resolving issues with manufacture and
`the controls section of the original NDA. In the second Letter
`sent in December 2007, the FDA has requested that Pfizer
`provide additional clinical data in accordance with its policy of
`non-inferiority trials, as discussed above for faropenem daloxate
`33. In addition, Pfizer are addressing questions regarding the
`length of storage time following reconstitution of dalbavancin 34
`and deviations from current good manufacturing practices
`(cGMP) at a third-party manufacturer not specifically related to
`the production of 34. Telavancin (TD-6424) 35 is a semi-
`synthetic derivative of vancomycin 38 discovered by Theravance,
`which is being developed in partnership with Astellas.144–147
`Telavancin 34 has a dual mode of action though disruption of
`plasma barrier membrane functions in addition to inhibition of
`cell wall synthesis. Theravance submitted an NDA in December
`2006 and an MAA in May 2007 for use against Gram-positive
`cSSSIs, especially MRSA. The FDA issued an Approvable
`Letter in October 2007 that detailed third-party cGMP compli-
`ance issues not specifically related to telavancin 34, requested
`a labelling revision and a reanalysis of clinical data or additional
`clinical data.148 Telavancin 34 is also being evaluated in Phase III
`treatment of HAP. Oritavancin (NuvocidÔ,
`trials
`for
`LY-333328) 35 is a semi-synthetic derivative of the vancomycin
`analogue chloroeremomycin 40 being developed by Targanta
`Therapeutics that was discovered by Eli Lilly.149,150 Phase III
`trials of oritavancin 35 for the treatment of cSSSIs have been
`completed and an NDA was filed in February 2008.151 Targanta
`also has Phase II trials in progress for the treatment of catheter-
`related bacteraemia and nosocomial pneumonia.
`Ramoplanin factor A2 (known as ‘‘ramoplanin’’) 41, which is
`the major component of the lipopeptide antibiotic complex
`produced by Actinoplanes sp., exerts its antibacterial activity
`by binding to the peptidoglycan intermediate Lipid II (C35-
`MurNAc-peptide-GlcNAc) and disrupting bacterial cell wall
`synthesis.152–156 Oscient Pharmaceuticals licensed the North
`American right for ramoplanin from Vicuron and have evaluated
`41 in Phase II trials for the treatment of Clostridium difficile-
`associated diarrhoea (CDAD). Oscient are currently looking to
`out-license, co-develop or sell the rights.
`NXL-103 (XRP2868), an orally available 70 : 30 mixture of
`two semi-synthetic streptogramins, flopristin (RPR132552A,
`streptogramin A-type) 42 and linopristin (RPR202698, strep-
`togramin B-type) 43, discovered by Sanofi-Aventis,
`is being
`evaluated by Novexel in Phase II trials for respiratory tract and
`respiratory infections.157–159 Streptogramins cause inhibition of
`bacterial protein synthesis through the synergistic binding of its
`streptogramin A and streptogramin B components to different
`sites on the peptidyltransferase domain of the 50S ribosomal
`subunit. The resistance mechanisms of each streptogramin type
`are different due to their distinct binding sites and chemical
`dissimilarity. NXL-103 has been reported to be approximately 4
`times more potent than SynercidÒ, an injectable streptogramin
`antibiotic consisting of a 70 : 30 mixture of dalfopristin and
`quinupristin launched by Sanofi-Aventis in 1999.
`In July 2007, MerLion Pharmaceuticals announced the
`commencement of Phase I trials of the lipopeptide antibiotic
`friulimicin B 44. Friulimicins are calcium-dependant antibiotics
`that have excellent activity against a range of Gram-positive
`
`bacteria and exert their antibacterial activity through complex
`formation with bactoprenol-phosphate, leading to the interrup-
`tion of peptidoglycan and teichoic acid biosynthesis.160–162 This
`mechanism is different to the marketed calcium-dependant
`antibiotic, daptomycin (CubicinÔ, Cubist Pharmaceuticals),
`suggesting that there would be little cross-resistance between
`both compounds. The friulimicin and amphomycin antibiotic
`complex produced by Actinoplanes friuliensis was first reported in
`a 1993 patent160 and in more detail in a 2000 paper.161 Friuli-
`micins only differ from amphomycins by virtue of containing
`asparagine rather than aspartic acid as the exocyclic amino acid
`residue. In late 2005, the crystal structure of the amphomycin
`tsushimycin (A-1437 B) 45, the aspartic acid analogue of friuli-
`micin B 44, was published, which confirmed the structure and
`absolute configuration of these compounds.163 Readers should
`consult
`the excellent review ‘‘Natural products to drugs:
`daptomycin and related lipopeptide antibiotics’’ for a detailed
`background of related lipopeptides.164
`Moli1901 (duramycin, 2262U90) 46 is an actinomycete-
`derived 19-residue lantibiotic first isolated in 1950, whose struc-
`ture was first proposed in 1958165 and later revised in 1990.166 In
`1996, Burroughs Welcome and the University of North Carolina
`patented the use of Moli1901 46 in an aerosol form for the
`treatment of cystic fibrosis, and Lantibio has licensed this patent.
`Moli1901 46 has been shown to increase chloride transport and
`fluid secretions when applied to airway epithelium in vitro, which
`increases chloride permeability in the nasal epithelium of healthy
`individuals and subjects with cystic fibrosis.167,168 In March 2007,
`AOP Orphan Pharmaceuticals AG and Lantibio announced
`positive results from European Phase II trials investigating
`aerosolized Moli1901 46 in adolescents and adults with cystic
`fibrosis.
`In addition, Lantibio has been investigating an
`ophthalmic solution of Moli1901 46 in Phase II trials in the US.
`The structure of the cationic peptide omiganan 47 is based on
`the potent antibacterial and antiviral peptide indolicidin 48,
`which was originally purified from the cytoplasmic granules of
`bovine neutro