The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 1: 5,6,11,11a-Tetrahydro-1H-imidazo[1‘,5‘:1,6]pyrido[3,4-b]indole-1,3(2H)-dione Analogues
| Autor: | Alain Claude-Marie Daugan, Francois Hyafil, Jorge Kirilovsky, Hervé Coste, Anne-Charlotte de Gouville, Cécile Ruault, Richard Frederic Labaudiniere, Pascal Grondin |
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| Rok vydání: | 2003 |
| Předmět: |
Phosphodiesterase Inhibitors
Stereochemistry Hydantoin Blood Pressure Chemical synthesis Muscle Smooth Vascular Tadalafil Structure-Activity Relationship chemistry.chemical_compound Isomerism 3' 5'-Cyclic-GMP Phosphodiesterases In vivo Rats Inbred SHR Drug Discovery Animals Structure–activity relationship Cyclic GMP Cyclic Nucleotide Phosphodiesterases Type 5 Indole test biology Chemistry Hydantoins Phosphodiesterase Rats Enzyme inhibitor Drug Design biology.protein Molecular Medicine Cattle Indicators and Reagents Lead compound Carbolines |
| Zdroj: | Journal of Medicinal Chemistry. 46:4525-4532 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm030056e |
| Popis: | Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-beta-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs PDE1-4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy. |
| Databáze: | OpenAIRE |
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