title: KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5.
abstract: The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K(i)=0.16 nM) more potently than sildenafil (K(i)=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 microM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 microM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 microM sildenafil did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, 411-8731, Shizuoka, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hirose
authors.forename: H
authors.initials: H
authors.lastname: Okumura
authors.forename: A
authors.initials: A
authors.lastname: Yoshimatsu
authors.forename: J
authors.initials: J
authors.lastname: Irie
authors.forename: Y
authors.initials: Y
authors.lastname: Onoda
authors.forename: Y
authors.initials: Y
authors.lastname: Nomoto
authors.forename: H
authors.initials: H
authors.lastname: Takai
authors.forename: T
authors.initials: T
authors.lastname: Ohno
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D015394:Molecular Structure; D005996:Nitroglycerin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011687:Purines; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011687:Purines; D011799:Quinazolines; D013450:Sulfones; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005996:Nitroglycerin; D006152:Cyclic GMP; C443180:KF 31327