Journal ArticleDOI
The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues.
Alain Claude-Marie Daugan,Pascal Grondin,Cécile Ruault,Anne-Charlotte de Gouville,Hervé Coste,Jean Michel Linget,Jorge Kirilovsky,Francois Hyafil,Richard Frederic Labaudiniere +8 more
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TLDR
The piperazinedione 12a, tadalafil, has been identified as a highly potent PDE5 inhibitor with high selectivity for PDE4 vs PDE1-4 and PDE6 and the cis-(6R,12aR) enantiomer displaying the highest PDE 5 inhibitory activity.Abstract:
Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).read more
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Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.
TL;DR: By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.
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2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products.
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A review on recent developments of indole-containing antiviral agents.
TL;DR: This review focused on the recent development of indole derivatives as antiviral agents and summarized the structure property, hoping to inspire new and even more creative approaches to discover novel drugs with different modes of action.
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Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments
Thérèse Keravis,Claire Lugnier +1 more
TL;DR: The investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies.
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The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease
TL;DR: It is proposed that to optimally alleviate this motor complication of Parkinson’s disease, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system.
References
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Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission
TL;DR: This work studied the smooth-muscle relaxant responses to stimulation by an electrical field and to nitric oxide to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection.
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Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
TL;DR: 5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum.
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Expression of rat cgmp-binding cgmp-specific phosphodiesterase mrna in purkinje cell layers during postnatal neuronal development
Jun Kotera,Noriyuki Yanaka,Kotomi Fujishige,Yuji Imai,Hiroyuki Akatsuka,Tohru Ishizuka,Keisuke Kawashima,Kenji Omori +7 more
TL;DR: It is suggested that cGB-PDE plays important roles not only in regulating the relaxation of vascular vessels, but also in establishing neuronal networks in the cerebellum at an early postnatal stage.
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Characterization of a novel potent and specific inhibitor of type V phosphodiesterase.
Hervé Coste,Pascal Grondin +1 more
TL;DR: It is shown that intracellular cGMP levels are mainly controlled by PDE V, rather than by egression in RSMC, and DMPPO is, therefore, a useful tool for determining the role of Pde V in the control of cG MP levels in living cells and tissues.