title: 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.
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).
authors.affiliation: Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 Avenue du Québec, 91951 Les Ulis Cedex, France.
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: Jean Michel
authors.initials: JM
authors.lastname: Linget
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* / Q000493:pharmacokinetics / 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; D008958:Models, Molecular; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / 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