title: 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.
abstract: 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.
authors.affiliation: Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 Avenue du Québec, 91951 Les Ulis Cedex, France. acd9791@gsk.com
authors.forename: Alain
authors.initials: A
authors.lastname: Daugan
authors.forename: Pascal
authors.initials: P
authors.lastname: Grondin
authors.forename: Cécile
authors.initials: C
authors.lastname: Ruault
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Le Monnier de Gouville
authors.forename: Hervé
authors.initials: H
authors.lastname: Coste
authors.forename: Jorge
authors.initials: J
authors.lastname: Kirilovsky
authors.forename: François
authors.initials: F
authors.lastname: Hyafil
authors.forename: Richard
authors.initials: R
authors.lastname: Labaudinière
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D006152:Cyclic GMP / Q000096:biosynthesis; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D015195:Drug Design; D006827:Hydantoins / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007536:Isomerism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D006827:Hydantoins; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP