`Therapeutic Pat ents
`
`Review
`
`Cardiovascular & Renal
`
`Inhibitors of PDEl and PDES cGMP phosphodiesterases:
`patents and therapeutic potential
`
`Edmund Sybertz & Michael Czarniecki
`
`Cyclic 3'5'-guanosine monophosphate (cGMP) is a key second
`messenger involved in the processes of intracellular signalling.
`Steady state levels of cGMP are modulated through a balance
`between the rates of formation and degradation of the nucleo(cid:173)
`tide. A potential therapeutic approach to manipulation of cGMP
`is the inhibition of the phosphodiesterases PDEl and PDE5.
`PDE5 inhibitors have been targeted by many companies and
`have resulted in a large number of patents. The disclosed
`inhibitors cover an eclectic range of polycyclic nitrogen hetero(cid:173)
`cycles. Activities reported show ICso values in the low nanomo(cid:173)
`lar to subnanomolar range. A wide range of tissue, cellular and
`in vivo effects are also reported for these PDE5 inhibitors. By
`contrast, only a very few patents have appeared which claim
`PDEl inhibitory activity. The potential use of PDEl and PDE5
`inhibitors in the treatment of coronary artery dtease, hyperten(cid:173)
`sion, congestive heart failure. erectile dysfunction and pulmo(cid:173)
`nary hypertension is discussed.
`
`Exp. Opin. Ther. Patents (1997) 7(6):631-639
`
`1. Introduction
`
`Cyclic 3'5'-guanosine monophosphate (cGMP. 1, Fig(cid:173)
`ure 1) is a key second messenger involved in proc(cid:173)
`esses of intracellular signalling [1]. cGMP can influence
`cell function through:
`
`• activation of a distinct family of protein kinases
`
`• modulation of ion conductance via cyclic nucleo(cid:173)
`tide gated ion channel s
`
`•
`
`the regulation of phosphodiesterases which influ-
`ence steady state levels of cGMP and cAMP
`
`Steady state levels of cGMP are modulated through a
`balance between the rates of formation and degrada(cid:173)
`tion of the nucleotide. Formation of cGMP is governed
`by soluble and membrane receptor guanylate cyclases.
`The former is stimulated by nitric oxide (NO) from
`both endogenous (e.g. , via activatio n of nitric oxide
`synthetases [NOSJ) or exogenous (e.g., via nitrovaso-
`
`dilators) sources [2[ . The receptor guanylate cyclases
`are activated via natriuretic peptides, guanylin and
`bacterial enterotoxins.
`
`cGMP regulates the function of many cell types. In
`smooth muscl e, cGMP provokes relaxation and inhi(cid:173)
`bition of cell growth [3,4]. In endothelium , nitric oxide
`and cGMP inhibit the adherence of circulating blood
`cells [5] . In platelets, cGMP inhibits aggregation [6]. In
`sensory cells, cGMP stimulates sodium and potassium
`flux through specific channels leading to changes in
`transmission of information related to light, smell and
`taste [7]. In epithelial cells, cGMP stimulates sodium
`efflux, resulting in diuresis, natriuresis in the kidney,
`and fluid and electro lyte loss in the gastrointestinal
`tract [8]. In the heart, cGMP modulates cellular excit(cid:173)
`ability through regulation of potassium and calcium
`conductances [9, 10]. In the CNS, cGMP has been
`implicated in the mediation of glutamatergic neuro(cid:173)
`transmission and synaptic plasticity [11] .
`
`631
`1997 © Ashley Publications ltd. ISSN 1354-3776
`
`INTELGENX 1026
`
`
`
`632 Inhibitors of PDEI and PDE5 cGMP phosphodiesterases- Sybertz & Czamiecki
`
`F igu re I : cGMP and prototype inhibitors ofPDEI and PDE5.
`
`C2H50 2C
`
`-
`
`~ -" CH3
`
`HN~O)
`CJ~N~O
`
`U-.. ~ No
`
`CO H
`2
`
`1
`cGMP
`
`2
`Vinpocetine
`
`3
`Zaprinast
`
`4
`E4021
`
`Tab le I: Major classes of cyclic nucleotide phosphodiesterases.
`
`POE
`
`Substrate
`
`Gene products
`
`I
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`cGMP
`cAMP
`
`cGM P
`cAMP
`
`cAMP
`
`cAMP
`
`cGMP
`
`cGMP
`
`cGMP
`
`3
`
`I
`
`2
`
`4
`
`2
`
`3
`
`I
`
`Regulatory
`mechanisms
`
`CaM dependent
`
`Tissue distribution
`
`Vascular tissue, brain, heart, kidney, lung,
`pancreas, circulating blood cells
`
`Stimulated by cGMP
`
`Adrenal cortex, platelet, vascular tissue,
`heart, lung
`
`Inhibited by cGMP
`
`Heart, vascular tissue, liver, platelet,
`adipocyte
`
`cAMP specific
`
`Heart, kidney, brain, gastrointestinal tract,
`liver, lung, c irculating blood cells
`
`cGMP specific
`
`Platelet, vascular tissue, lung
`
`cGMP specific
`
`Retinal rods , cones, kidney
`
`Unknown
`
`Skeletal muscle, T -cells
`
`cGMP modulation has been exploited for therapeutic
`purposes for over 100 years. Nitrovasodilators are
`important drugs in the treatment of cardiovascular,
`gastrointestinal and urogenital disorders [12]. Although
`effective, these agents suffer from several limitations,
`including vasodilator-related side-effects such as hy(cid:173)
`potension, headache and nausea as well as the poten(cid:173)
`tial to develop tolerance with long-term or high dose
`treatment. Natriuretic peptides have been evaluated for
`clinical utility in hypertensio n and congestive heart
`failure [13]. However, these agents have limited utility
`due to their peptidic nature, need for injectable ad(cid:173)
`ministration and, in the case of congestive heart failure,
`the development of tolerance to their renal effects.
`Alternative mechanisms for modulating the activity of
`natriuretic peptides are being explored and may offer
`novel approaches for treatment of hypertension, con(cid:173)
`gestive heart failure and gastrointestinal disorders.
`
`An alternative approach to the stimulation of guanylate
`cyclase is the inhibition of phosphodiesterases in(cid:173)
`volved in the degradation of cGMP. At least seven
`families (Table I) of phosphodiesterases have been
`identified [14]. These share common structural fea(cid:173)
`tures, including a highly conserved amino acid se-
`
`quence at the hydrolytic site. Selective inhibitors have
`been developed for several of the families of PDE.
`PDE3 selective inhibitors have been targets for cardiac
`insufficiency, whereas PDE4 inhibitors are being pur(cid:173)
`sued as a novel approach to asthmatic, pulmonary and
`inflammatory disorders [15[. The major isoforms in(cid:173)
`volved in the degradation of cGMP are PDE1 , 2, 5 and
`6.
`
`PDE1 is a calmodulin dependent phosphodiesterase
`[14,16] . Several isoforms ofPDE1 have been identified
`and are distributed in heart, lung , kidney, circulating
`blood cells and smooth muscle cells. A distinct PDE1
`found in the brain, which hydrolyses both cAMP and
`cGMP, may play an important role in modulation of
`neurotransmission. In vascular smooth muscle, PDE1
`plays a major role in the hydrolysis of cGMP, and PDE1
`inhibitors exert potent vasodilator actions. cGMP binds
`to and is selectively hydrolysed by PDE5 and 6. PDE5
`is disttibuted in lung, kidney, spleen, platelets, endo(cid:173)
`thelial cells and smooth muscle cells, and plays a key
`role in hydrolysis of cGMP in these tissues. Potent
`inhibitors of PDE5 with selectivity over PDEl, 2, 3 and
`4 have been discovered and evaluated in both clinical
`and preclinical settings.
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Ther. Patents (1997) 7(6)
`
`INTELGENX 1026
`
`
`
`Cardiovascular & Renal - Review 633
`
`POE6 is a related. but distinct gene product from POE5
`[1 6]; it is distributed predominantly in sens01y tissues.
`In retinal tissue , lig ht activates rhodopsin, which in
`turn signals transdu cin
`to ac tvate POE6, lead ing to
`reduction of cGMP levels and closure of the cyclic
`nuc leotide gated ion channel. Mutations w hich inhibit
`the function of retinal POE6 lead to retinal degenera(cid:173)
`tion and blindness in animals and man . POE5 inhibi(cid:173)
`(4) . also inhi bit POE6 (HS Ahn,
`tors, e.g., E4021
`unpublished observations) . The potential safety impli(cid:173)
`cations of this action remain to be defined.
`
`2. Inhibitors of cGMP phosphodiesterases
`(PDEl and PDES)
`
`2.1 PDES inhibitors
`
`The alkaloid vinpocetine (2) is a weak but selective
`inhibitor of POEl but does not inh ibit POE5 or the
`cAMP hydrolysing enzyme, POE3. Zaprinast (also
`known as M&B 22948) (3) is an inhibitor of POE5
`to POE3. More recently,
`which is selective relative
`E4021 (4) was reported as a very potent (ICso = 4 nM)
`inhibitor of PDE5 with high selectivity relative to POE 1.
`2, 3 and 4. Very little patent activity or published
`research has explored the activity of 2. In contrast to
`vinpocetine, 3 and 4 have formed the basis for a wide
`ranging exploration of structure-activity relationsh ips
`(SAR) related to these core structures.
`
`Patent activity relating to cGMP phosphodiesterases
`from 1992 to 1995 has been extensively reviewed in
`two recent articles [1 6,18]. This review will focus on
`those new inhibitors of cGMP hydrolysing POEs which
`have emerged, primarily in the patent literature, be(cid:173)
`tween 1995 and early 1997. Most of the activity has
`surrounded inhibitors of POE5 (Table 2) with a much
`smaller representation for POE!. Structures shown in
`Table 2 represent, for the most part, the most potent
`POE5 inhibitors exemplified within the patent descrip(cid:173)
`tion . The structures which have been described repre(cid:173)
`sent an eclectic collection o f polycyclic nitro gen
`heterocylic compounds. Some of these follow well
`know lead structures such as zaprinast (3) and E402 1
`(4) , but many strike into new structural territory.
`
`Pyrazolo analogues (5 - 9) of zaprinast are potent and
`selective inhibitors of PO E5. Sanofi-Winthrop has pat(cid:173)
`ented 6-benzyl (5) and 6-phenyl (6) derivatives with
`ICso values as low as 1.8 nM. A significant amount of
`SAR is disclosed in th ese series with in vitro POE5
`activity reported for about 80 analogues between the
`two patents [100,101] . These inhibitors are reported to
`decrease blood p·essure and reverse nitroglycerine
`tolerance in the SHR. However, since the drugs were
`administered only by the intravenous route, the paten-
`
`tial for these POE5 inhibitors to be orally effecti ve is
`unknown. Zaprinast (3) has been shown to be effec(cid:173)
`tive only at very high oral doses, e.g .. 200 mg/kg/day
`[1 9].
`
`Urea (7) or sulfonamide (8.9) substitution on the
`pendant 6-(2-propyloxy)-phenyl is a strategy disclosed
`by three companies [102-105]. In each case, the best
`inhibitors have ICso values < 5 nM for POE5. These
`patents' clalmed biological activities suggest that this
`type of modification results in good oral activity.
`Indeed, Glaxo has published extensively ·on the SAR
`of compounds related to 8 , and many co mpounds are
`reported to reduce blood pressure over a five hour
`period when administered to SHR at 5 mg/kg p.o. [20].
`Pfizer has advanced one member of this class, silde(cid:173)
`nafil (9). to clinical trials for
`the treatment of male
`impotence [2 1]. In an aggressive strategy to protect this
`potentially large commercial franc hise, Pfizer has filed
`broad use patents on pyrazo lopyrimidino nes, bicyclic
`heterocycles, and, in fact, essentially all POE5 inhibi(cid:173)
`tors claimed in a wide variety of patents filed by other
`pharmaceutical companies [106].
`
`The potent and selective POE5 inhibitor E4021 (4) has
`been the prototype for new structures (10 - 14) which
`have appeared in five recent patents. Ono has ex(cid:173)
`plored novel quinazolines (10) , bicyclic pyrimidines
`(11) . and pyrimidines (12) as inhibitors of POES
`[107-111].
`
`An interesting additional claim within these patents is
`the inhibition of TXAz synthetase activity. The synthe(cid:173)
`sis and SAR of structures related to 10 have also been
`detailed in a recent publication [22]. The best com(cid:173)
`pounds in this series show ICso values in the low
`nanomolar range and more than 1000-fold selectivity
`for POE5 relative to the other four POE types. The
`reported TXAz synthetase inhibitor activity is, however,
`somewhat more modest. with inhibition only being
`significant in the 11M range. Because of this separation
`in in vitro activity, it is not clear whether both enzymes
`would be inhibited upon administration of a drug at
`doses which would show effects from POES inhibition.
`Eisai continues to fo llow-up E4021 (4) with additional
`patent filings on heterocyclic variants (13) and ring
`opened analogues (14) of the 1,3, 7-trisubstituted qui(cid:173)
`nazoline lead [11 2,1 13]. Of particular note are the
`structures related to 13 (ICso = 12 pM) of which several
`are claimed to have highly potent POE5 activity.
`Compound 12, as well as 13, clearly su ggests that the
`bicyclic nitrogen heterocycles so commonly associated
`with POE5 inhibitors are not an absolute requirement
`for potent inhibitory activity.
`
`The other POES inhibitors which have been patented
`in this period represent an eclectic group with no
`common structural theme. Glaxo has disclosed novel
`
`© Ashley Publi cations Ltd. All rights reserved.
`
`Exp. Opin. Ther. Patents ( 1997) 7(6)
`
`INTELGENX 1026
`
`
`
`634 Inhibitors of PDEl and PDE5 cGMP phosphodiesterases- Sybertz & Czamiecki
`
`Table 2: PDE5 inhibitors: structures and biological properties.
`
`Compound
`number
`
`Structure
`
`PDESICso
`(nM)
`
`Additional biological data
`
`:Y:c~
`
`HN
`
`$" b
`H,C~~N b
`
`OCH 3
`
`:Y:CH,
`I
`
`~
`CH3
`H3C~O HN~N
`
`HNI(N
`
`0
`
`0
`
`CH
`
`HC
`
`'~~ I 'N
`
`~N N ' 0 CH3
`:r. 3
`
`"N
`
`N.
`CH3
`
`23
`
`1.6
`
`1.5
`
`3
`
`SHR: 30% reduction in MAP after iv. dosing at I 0
`mg/kg
`SHR: 69% reversa l of nitroglycerin tolerance after
`iv. dosing@ 1.0 mg/kg
`
`SHR: I% reduction in MAP after iv. dosing at I 0
`mg/kg
`SHR: 49% reversal of nitroglycerin tolerance after
`iv. dosing@ 1.0 mg/kg
`
`ECso = 0.35l!M for relaxation of rat aortic smooth
`muscle
`SHR: AUC= 129 mmHg.h for 0- 5 h after p.o.
`dosing@ 5.0 mg/kg
`
`3.6
`
`PDEI: ICso = 260 nM
`PDE3 : ICso = 65000 nM
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`NHS02CH3
`
`0
`
`CH
`
`H3C~O HN:-:-~N 3
`<rN N
`H3C.N l
`~N, / NH
`S02
`
`(
`CH3
`
`H~~ 0·cH,
`
`~
`
`N
`N~N""'
`l:::JN
`
`46
`
`TXAz synthetase: ICso = 2.4 11M
`
`HN:CXO)
`
`a :N ~ 0
`I~
`N N~
`l:::JN
`
`24
`
`TXAz synthetase: 63% inhibition@ I 0 11M
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Ther. Patents (1997) 7(6)
`
`INTELGENX 1026
`
`
`
`Table 2: PDE5 inhibitors: structures and biological properties (continued).
`
`Compound
`number
`
`Structure
`
`PDES ICso
`(nM)
`
`Additional biological data
`
`Cardiovascular & Renal - Review 635
`
`~XC> 14
`N
`::::....
`~ N N~
`~N
`
`0
`
`TXA2 synthetase: 90% inhibition @ 10 IJ.M
`
`12
`
`13
`
`14
`
`HN:CXCI
`
`""'-
`
`I
`-"N
`
`3
`
`NC~N "'I OCH
`I
`Q
`
`CONH 2
`
`0
`II
`NC«NUC I
`I
`I
`H
`~ OCH
`NH
`
`::::....
`
`CH3
`
`N
`
`H
`
`~
`
`a
`0
`oJ
`
`::; 0.1 1
`
`0.7
`
`2
`
`ECso = 0 .2 IJ.M for elevation of cGMP in rat aortic
`smooth muscle
`SHR: AUC= 135 mmHG.h forO- 5 h after p.o.
`dosing @ 5 mg/kg
`
`< 100
`
`ICso < 100 nM for relaxation ofprecontracted rat
`VSM
`ICso < I 00 nM for inhibition of proliferation of rat
`vSMC
`Inhibition of vasopressin induced vasospasm
`>50%@ 10 mg/kgp.o .
`
`10
`
`ICso = 0.5 (.l.M for inhibition of proliferation of rat
`A 10 cells
`!Cso = 0.04 (.l.M for inhibition of proliferation of
`human fibroblasts
`ICso = 3.0 (.l.M for inhibition of proliferation of
`mouse T -cells
`ICso = 0. 79 (.l.M for inhibition of proliferation of rat
`mesangial cells
`
`0~'0H '
`~ 15
`vo
`)a ~
`--
`
`16
`
`0
`
`H2N
`
`?'
`
`N
`::::.... I ,1
`
`H3 C
`
`0
`
`CH 3
`
`CH 3
`
`FN
`
`n"Mo-c9-J"~
`
`17
`
`Cl
`
`~ ~ /;
`
`N
`
`d
`
`© Ashley Publications Ltd . All rights reserved.
`
`Exp. Opin. Tiler. Patents ( 1997) 7(6)
`
`INTELGENX 1026
`
`
`
`636 Inhibitors of PDEI and PDE5 cGMP phosphodiesterases - Sybertz & Czamiecki
`
`Table 2: PDE5 inhibitors: structures and biological properties (continued).
`
`Compound
`number
`
`Structure
`
`PDES ICso
`(nM)
`
`Additional biological data
`
`18
`
`19
`
`20
`
`HN~
`~:ceN~
`J
`I
`s=(
`N ~ ""
`(
`N
`
`CH3
`
`0.18
`
`PDEl : 58% inhibition @ I 0 11M
`PDE2: 60% inhibition @ 10 11M
`PDE3: ICso = llOOnM
`PDE4: ICso> 10,000 nM
`
`N
`
`'2 NH
`cCc .N
`0 tO
`H3CN~N;)
`~N N
`()
`
`)
`H3C
`
`2.2
`
`100
`
`PDEl: ICso = 100 nM
`SHR: 40 mmHg reduction in MAP @ 25 mg/kg p.o.
`
`tetracyclic diketopiperazines (15) with potent POE5
`activity and oral activity in the SHR [ 114] . The POES
`activity appears to be dependent on the absolute
`stereochemistry of the ring fu sed diketopiperazine.
`The most activestereochemistl)' is that which is shown
`in compo und 15. Fujisawa has filed a patent applica(cid:173)
`tion on the chemically novel indoles related to struc(cid:173)
`ture 16 [115]. Unfortunately, no SARis available in this
`patent and activity is only reported as< 100 nM for the
`most potent compounds. Otsuka has claimed potent
`POES inhibition for the class of molecules rerresented
`by 17 [116]. In addition, this mo lecule has shown
`antiproliferative effects in several cell types in the 0.04
`- 3.0 11M range. Kyowa Hakko Kogyo has disclosed
`novel stru ctures (e.g., 18) which incorporate elements
`of the quinazoline inhibitors and the purine substrate
`[117 , 118]. Th is hybrid structure shows more than 6000-
`fold selectivity when compared to POE1 , 2, 3, 4.
`Sanofi-Winthrop has a patent on structures (e.g., 19)
`which combine elements of the quinazolines as well
`as the pyrazolopyrimidines [119, 120]. Finally, Schering(cid:173)
`Plough has received a US patent on novel tetracyclic
`guan ines with modest POE5 activity and oral anti-hy(cid:173)
`pertensive activity in the SHR [1 21] . An interesting
`
`potential extra benefit of these compounds is inhibi(cid:173)
`tion of POE! with the same potency as POE5.
`
`2.2 PDEl inhibitors
`
`Very little activity in either the patent or published
`literature has appeared in recent years on POE1 inhibi(cid:173)
`tors. As discussed above, compound 20 is a dual
`inhibitor of both POE! and POE5 , with oral activity in
`the SHR [121] . Sanofi-Winthrop has published on the
`POEl inhibitory activity of a series of imidazotriazones
`[23]. Compo und 21 (Table 3) inhibits POE1 with an
`ICso = 85 nM. However, this series showed limited
`selectivity with 21 , demonstrating 3.4-fold selectivity
`relative
`to POE3 and 36-fold selectivity relative
`to
`POES; Interestingly , no patent activity was ob~rved
`for this compound class. Although, Eisai h as concen(cid:173)
`trated on inhibitors of POE5, one patent on related
`quinazolines appears to show modest inhibition of
`POEl [1 22]. Compound 22 inhibits POE1 with an ICso
`= 170 nM . However, since the activity for other POE
`isozymes is not reported , it
`is not clear if these
`compounds are selective POE! inhibitors or retain
`some POE5 activity.
`
`© Ashley Publications Ltd . All ri ght s res erved.
`
`Erp. Opin. Ther. Parents (1997) 7(6)
`
`INTELGENX 1026
`
`
`
`Table 3: PDE I inhibitors: structures and biological properties.
`
`Compound
`number
`
`Structure
`
`PDES ICso
`(nM)
`
`Additional biological data
`
`Cardiovascular & Renal - Review 637
`
`20
`
`21
`
`22
`
`100
`
`PDE5: ICso = IOOnM
`SHR: 40 mmHg reduction in MAP @25 mg/kg p .o.
`
`85
`
`PDE3: ICso = 290 nM
`PDE5: ICso = 3100 nM
`
`170
`
`3. Therapeutic utility of PDEl and PDES
`inhibitors
`
`3.1 Coronary artery disease
`
`Inhibition of PDEl, PDE5 or a combination of both
`offers potential utility in the treatment of angina pec(cid:173)
`toris and coronary artery disease. Inhibitors of PDEl
`and 5 dilate coronary arteries [ 16,17]. In addition, these
`agents are able to potentiate endothelial dependent
`vasorelaxation by enhancing activity of the cGMP
`generated from NO activation of guanylate cyclase [16].
`Indeed, vasodilation induced by PDE5 and PDEl
`inhibitors is at least in patt mediated through NO. as
`inhibitors of NOS or endothelial denudation reduce or
`eliminate the response. Since endothelial dependent
`vasodilation is impaired in coronary artery disease,
`PDEI and 5 inhibitors may in part restore this reduced
`endothelial responsiveness. In addition, PDEI and 5
`inhibitors exert antiplatelet and antithrombotic activity
`which could potentially influence in a positive fashion
`unstable forms of angina pectoris [16, 24,25]. The PDE5
`inhibitor E4021 prevents ischaemia in guinea-pig [26].
`
`cGMP modulates the growth and proliferation of vas(cid:173)
`cular smooth muscle cell s and the adherence of circu(cid:173)
`lating cells to the injured vascu lar endothelium. In light
`
`of these actions. modulators of cGMP may influence
`atherosclerosis and restenosis post PTCA or stenting.
`Elevation of NO through arginine supplementation has
`been shown to produce beneficial effects in animal
`models of atherosclerosis [27]. Inhibitors of PDE! and
`5. vja inhibition of cGMP hydrolysis. prevent intimal
`hyperplasia following angioplasty in the rat carotid
`artery injury model. This effect appears to be mediated
`through PDEI, as the PDEI/5 inhibitor SCH 51866 {but
`not the selective PDE5 inhibitor E4021) prevents the
`response [25] .
`
`3.2 Hypertension
`
`Inhibitors of PDE I and 5 are potent vasodilator agents
`and, as such, may lower systemic blood pressure in
`hypertensive states. In experimental models. inhibitors
`of PDEl and 5 lower blood pressure, and this antihy(cid:173)
`pertensive effect appears to be mediated, at least in
`part, through NO, as it can be attenuated by inhibitors
`of NOS [16,25]. Since PDEI and 5 inhibitors exert
`antithrombotic effects and PDEl inhibition inhibits
`vascu lar growth, there is the possibility that such
`agents may alter the long-term vascular consequences
`of hypertension. On the down-side, PDEl inhibitors
`elicit a reflexively mediated increase in heart rate
`wh ich may limit their overall utility.To date, no PDE
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Ther. Patents ( 1997) 7(6)
`
`INTELGENX 1026
`
`
`
`638 Inhibitors of PDEI and PDE5 cGMP phosphodiesterases - Sybertz & Czamiecki
`
`inhibitor has been evaluated in human clinical hyper(cid:173)
`tension. The potential advantages of POE inhibition
`over existing forms of antihypertensive therapy need
`to be defined because safe, well-tolerated and effective
`agents currently exist for treatment of this disease.
`
`3.3 Congestive heart failure
`PDEl and 5 inhibitors may offer potential utility for the
`treatment of congestive heart failure. In congestive
`heart failure , natriuretic peptides are increased and
`endothelial dependent vasodilator mechanisms appear
`to be impaired. Modulation of cGMP through either
`natriuretic peptide activity or nitrovasodilator treat(cid:173)
`ment has been shown to exert beneficial actions in
`congestive heart failure. Because PDEl and 5 inhibitors
`do not influence cardiac contractility, they may be
`devoid of some of the adverse effects associated with
`POE3 inhibitors in this disease state. E4021 has been
`evaluated in a model of porcine congestive heart
`failure, and has been reported to exert beneficial
`haemodynamic and renal effects [28]. A key issue in
`congestive heart failure is to assure that hypotension
`due to excessive vasodilation does not offset any
`benefit gained from the attributes described above. To
`date , no PDEl or 5 inhibitors have been evaluated in
`human congestive heart fa ilure.
`
`3.4 Erectile dysfunction
`Impotence of vasculogenic origin is a highly prevalent
`disorder and there is a need for newer therapies to
`influence this. Penile erection is initiated through the
`engorgement of the corpus cavernosum. A major
`mediator of this is nitric oxide, which appears to be
`released from nitrergic nerves upon stimulation. The
`major POE involved in the degradation of cGMP in this
`tissue is PDE5. PDE5 inhibitors have been shown in
`animal and human stud ies to improve erectile function
`in impaired individuals. Sildefanil is curren tly under(cid:173)
`going Phase III evaluation for this indication [29].
`
`3.5 Pulmonary hypertension
`Chronic hypoxia results in a remodelling of the vascu(cid:173)
`lature of the pulmonary tree leading to elevated pul(cid:173)
`monary a1tery pressure and pulmonary hypertension
`[30] . Although relati vely rare, pulmonary hypertension
`is a serious disorder with one year mortality rates
`approaching fifty percent. In hypoxic states, endothe(cid:173)
`lial induced vasorelaxation is impaired and natriuretic
`peptides are released. NO per se, ANP, and EC 24.1 1
`inhibitors have all been shown to exert some benefit
`in this disease. POE5 inhibitors have been evaluated
`in this setting and have been shown to exert a bene(cid:173)
`ficial effect on pulmonary artery pressure and on the
`chronic remodelling which accompanies this disease
`[31].
`
`4. Therapeutic perspective
`
`Considerable potential exists for inhibitors of POEl
`and 5 in the treatment of human disease. It is clear that
`cGMP and agents which influence its formation or
`degradation can exert important pharmacological ef(cid:173)
`fects in animal models and in man. The key issue with
`this approach is to balance effi cacy with safety and
`tolerance. This has proven to be problematic in the
`search for safe and effective PDE3 and 4 inhibitors and
`remains to be established for PDEl and 5 inhibitors.
`
`Bibliography
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`Cyclic GMP synthesis, metabolism and function. In:
`Advances in Phannacology. Murad F (Ed.). Academic Press,
`New York, NY (1994) 26:1-35.
`
`MURAD F: Signal transduction using nitric oode and
`(1996)
`cyclic guanosine monophosphate.
`]AMA
`276:1189- 1192.
`
`WAMER TO, MITCHELL JA. SHENG H. MURAD F: Effects of
`cGMP on smooth muscle relaxation. Adv. Pharmacal.
`(1994) 26:17 1-194.
`
`YU SM. HUNG LM, C!-llA CHIH L: cGMP elevating agents
`suppress proliferation of vascular smooth muscle cells
`by inhibiting the activation of epidermal growth factor
`signalling pathway. Circulation (1997) 95:1269-1277.
`
`KUBES P. SUZUKI M. GRANGER ON: Nitric oxide: an
`endogenous modulator of leukocyte adhesion. Proc.
`Nad. A cad. Sci. USA (I 99 1) 88:587-590.
`
`MONCADA S. PALMER RMJ. HIGGS EA: Nitric oxide: physi(cid:173)
`ology, pathophysiology, and pharmacology. Pharmacal.
`Rev. (1991) 43:109-142.
`
`FINN JT. GRUNWALD ME, YAU KW: Cyclic nucleotide
`gated ion channels: an extended family with diverse
`functions. Ann. Rev. Physiol. (I 996) 58:395-426.
`
`VAANDRAGER AB. DEJONGE HR: Effect of cyclic GMP on
`intestinal transport. Adv. Pharmacal. (1994) 26:253-283.
`
`SHIRAYAMA T. PAPPANO AJ: Biphasic effects of in(cid:173)
`trapipette cyclic guanosine monophosphate on L-type
`calcium current and contraction of guinea pig ventricu(cid:173)
`lar myocytes . j Pharmacal. Exp. Ther. (1996) 279:1274-
`1281.
`
`SPERELAKIS N. TOHSE N. OHYA Y, MASAUDA H: Cyclic
`GMP regulation of calcium slow channels in cardiac
`muscle and vascular smooth muscle cells. Adv. Pharma(cid:173)
`cal. (1994) 26:217-252.
`
`HARTELL NA: Inhibition of cGMP breakdown promotes
`the induction of cerebellar long-term depression. j
`Neurosci. (1994) 16:2881-2890.
`
`ROBERTSON RM, ROBERTSON 0: Drugs used for the
`treatment of myocardial ischemia. In: Goodman and
`Gilman 's 7he Pharmacological Basis of Therapeutics. (Ninth
`Edition} Hardman JG & Limbird LE (Eds.) (1996) 759-781.
`
`STRUTHERS AD: Ten years of natriuretic peptide re(cid:173)
`search: a new dawn for their diagnostic and therapeutic
`use. Br. Med. j (1994) 308:1615-1619.
`
`© Ashley Publications Ltd. Al l rights reserved.
`
`Etp. Opin. Ther. Patents ( 1997) 7(6)
`
`INTELGENX 1026
`
`
`
`Cardiovascular & Renal - Review 639
`
`BUMS F. ZHAO AZ. BEAVO JA: Cyclic nucleotide phos (cid:173)
`phodiesteras es: Gene complexity , regulation by phos (cid:173)
`phorylation and phys iological implications. Adv.
`Phannacol. (J 996) 36 :29-48.
`
`RAEBUM D. SOUNESS J. TOMKINSON A. KARLSSON j:
`Isozyme-selective cycli c nucleotide phosphodiesterase
`inhibitors: bioche mis try, pharmacology, and the rapeu(cid:173)
`tic pote ntial in asthma. Prog Drug Res. {1993) 40:9-32.
`
`SYBERTZ EJ. CZARNIECKI M. AHN H: cGMP phos phodi (cid:173)
`esteras e inhibition: a n ew m echanism for discovery of
`therapeutic agents. Curr. Pharm. Design. (J 995) 1: 373-390.
`
`SAEKI T. ADACHI H. TAKANE Y, YOSHITAKI S, SOUDA S,
`SAIT O 1: A selective type V phosphodiesterase inhibitor,
`E 4021 , dilates porcine large coronary artery. j Pharma(cid:173)
`cal. £-.:p. Ther. (1995) 272 :825-831.
`
`CZARNIECKI M. SYBERTZ EJ. AHN H-S: Inhibitors of Type
`I and V phos phodies terase: elevation of cGMP as a
`therapeutic strategy. Annu. Rep. Med. Chem. (1996) 31:61-
`70.
`
`MCMAHON EG. PALOMO tv!A, MEHTA P. O LINS GM: De(cid:173)
`pressor and natriure tic e ffects of M&B 22,948, a
`guanosine cyclic 3', 5'-monophosphate-selective phos(cid:173)
`phodiest erase. j Pharmacal. £-.:p. Ther. (1989) 251:1000-
`1005.
`
`DUMAITRE B. DODOC N: Synthesis and cyclic GMP
`phosphodiesterase inhibitory activity of a seri es of
`j Med. Chem.
`6-phenylpy razolo[3 ,4-d)pyrimidones.
`(1 996) 39:1635- 1644.
`
`TERRETT N. BELL A. BROWN D. ELLIS P: Silde nafil (Viagra
`TM) , A potent a nd se lective inhibitor of type 5 cGMP
`phosphodiesterase w ith utility for the treatme nt of
`male erectile dysfunction . Biaorg. Med. Chem. Leu. (I 996)
`6:1819-1824.
`
`LEES. KON ISHI Y. YU D. MISKOWSKI T e1 a/.: Discovery
`of pote nt cyclic GMP phosphodiesterase inhibitors.
`2-Pyridyl- and 2-imidazo ly lquinazolines possessing cy(cid:173)
`clic GMP phosphodie ste ras e and thromboxane synthe(cid:173)
`sis inhibitory activiti es . j Med. Chem. (I 995) 38:3547-3557.
`
`HIASTA D. BODE D. COURT J. DESAI R. PAGANI E. SILVER
`P: Imidawtriazino n e inhibitors of the ci• -<:almodulin
`sensitive phos phodies te rase (PDE I) . Bioorg. Med. Chem.
`Lell. (I 997) 7:89-94.
`
`CHIU PJS. VEMULAPALLI S. CH INTALA Mel a!.: lnl1ibitio n
`of platelet adhesion and aggregation by E4021 , a type V
`phosphodies te rase inl1ibitor, in guinea-pigs. Naunyn
`Schmiedeberg's Arch. Pharmacal. (J 997) (I n Press).
`
`28.
`
`29.
`
`30.
`
`31.
`
`in the hypercholeste role mic rabbit . j Clin. Invest. (1992)
`901 :168
`
`KODAMA K. ADACHI H. YOSHITAKE S, SAITO 1: 68th
`meeting of jpn. Pharmacal. Soc. (I 995) 3-6.
`
`BOOLELL M. GEPIATEE S. GINGELL JC. ALLEN Mj: Silde(cid:173)
`nafil, a novel effective oral therapy for male erectile
`dysfunction. Br. j Ural . (1996) 78:257-26 1.
`
`RUBIN Lj: Primary pulmonary hypertension. New Engl.
`j Med. (1997) 336:111 -11 7.
`
`TAKAHASHI T. KAN DA T. INOUE M. SUZUJG T. KO(cid:173)
`BAYASHI I. KODAMA K. NAGAI R: A selective Type V
`phosphodiesterase inl1ibitor, E 4021, protects the de(cid:173)
`velopment of right ve ntricular overload and medial
`thickening of pulmonary arteries in a rat model of
`pulmonary hypertension. Life Sci. (I 996) 59:L37 1-L377.
`
`Patents
`
`100.
`
`SANOFI-WINTHROP. INC .. W09628429 (1 996).
`
`10 1.
`
`SANOFI-WINTHROP. INC .. W09628448 (1996).
`
`102.
`
`TA ISHO PHARMCEUTICAL CO. LTD .. jP8253484 (1 996).
`
`103.
`
`LABORATOIRES GLAXO SA, EP-636626-A 1 (1995).
`
`104.
`
`PFIZER LIMITED. W09 428902 (1994).
`
`105.
`
`PFIZER LIMITED. W096 16657 (1 996).
`
`106.
`
`PFIZER LI MITED. W096 16644 (1 996).
`
`107. ONO PHARMACEUTICAL CO. LTD .. US5436233 (1995).
`
`108. ONO PHARMACEUTICAL CO. LTD .. US5439895 (1995).
`
`109. ONO PHARMACEUTICAL CO. LTD .. EP-728759-A1 (I!ll6).
`
`11 0. ONO PHARMACEU TICAL CO. LTD .. EP-640599-A1 (I!ll5).
`
`111. ONO PHARMACEUTICAL CO. LTD .. US5525604 (1996) .
`
`11 2.
`
`EISA! CO. LTD .. W09605 ! 76 (1 996).
`
`11 3.
`
`EISA! CO . LTD . W095 ! 8097 (I 995).
`
`11 4.
`
`LABORAT OIRES GLAXO SA. 'Ml95 19978 (1 995).
`
`115.
`
`FUJISAWA PHARMCEUTICALCO. LTD .. W09632379 (1996).
`
`116. OTSUKA PHARMCEUTICAL CO. LTD .. W09703070 (1997).
`
`11 7. KYOWA HAKKO KOGYO CO . LTD .. W09626940 (1996).
`
`118. KYOWA HAKKO KOGYO CO. LTD .. W09506648 (1995).
`
`VEMULAPALLI S. WATKINS RW. CHINTALA M ela/.: Anti (cid:173)
`platelet and antipro life rative effects of SCH 51866, a
`novel typ e I and V phos phodiesterase inhibitor. j
`Cardiavasc. Phannacal. (I 996) 28:862-869.
`
`119.
`
`SANOFI-WINTHROP. INC .. US5488055 (1996).
`
`120.
`
`SANOFI-WINTHROP. INC .. W09628 159 (1 996).
`
`121.
`
`SCHERING -PLOUG H CO .. US5393755 (1 995) .
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`KO DAMA H. ADACHI H. MO RJ N. SAITO I: Effe cts of a
`novel, se lective and p ote nt phosphodiester ase type V
`inhibitor, E-4021 , on m yo cardial ische mia in gu inea
`pigs . Eur. j Pharmacal. (I 994) 263:93-99.
`
`27.
`
`COOKE JP. SINGER AH. TSAO P. ZERA P. ROWAN RA.
`BILLING HAM ME: Anti a the roge nic effects of ! -arginine
`
`122.
`
`EISA! CO. LTD .. W09507267 (1 995).
`
`Edmund Sybert z1 & Michael Czarniecki
`1 Author fo r correspondence
`Schering-Piough Research Institute. 20 15 Ga lloping Hill Road, Kenil(cid:173)
`wort h, NJ 07033, USA
`
`© Ashley Publi cat ions Ltd. All rights reserved.
`
`Exp. Opin Ther. Patents ( 1997) 7(6)
`
`INTELGENX 1026