Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: Methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533).
In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.
Choi
Hojin
H
Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea.
Lee
Jaekwang
J
Kim
Young Hoon
YH
Im
Dai Sig
DS
Hwang
In-Chang
IC
Kim
Soo Jin
SJ
Moon
Seung Kee
SK
Lee
Hong Woo
HW
Lee
Sung Sook
SS
Ahn
Soon Kil
SK
Kim
Sang Woong
SW
Choi
Nam Song
NS
Lee
Kyung Joo
KJ
D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D002219:Carbamates; D004791:Enzyme Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D011799:Quinazolines; C549138:methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5