ABSTRACT
A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Phosphodiesterase 5 Inhibitors/pharmacology , Pyridones/pharmacology , Pyrimidines/pharmacology , Animals , Dose-Response Relationship, Drug , Molecular Structure , Phosphodiesterase 5 Inhibitors/chemical synthesis , Phosphodiesterase 5 Inhibitors/chemistry , Pyridones/chemical synthesis , Pyridones/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rabbits , Structure-Activity RelationshipABSTRACT
5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800).
Subject(s)
Drug Design , Phosphodiesterase 5 Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Cattle , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Dogs , Humans , Hydrogen Bonding , Phosphodiesterase 5 Inhibitors/pharmacology , Pyrimidines/pharmacology , RabbitsABSTRACT
Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30=2.1 nM) and a high isozyme selectivity.
