title: Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: Methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533).
abstract: 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.
authors.affiliation: Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea.
authors.forename: Hojin
authors.initials: H
authors.lastname: Choi
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Lee
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Dai Sig
authors.initials: DS
authors.lastname: Im
authors.forename: In-Chang
authors.initials: IC
authors.lastname: Hwang
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Seung Kee
authors.initials: SK
authors.lastname: Moon
authors.forename: Hong Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Sung Sook
authors.initials: SS
authors.lastname: Lee
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Kim
authors.forename: Nam Song
authors.initials: NS
authors.lastname: Choi
authors.forename: Kyung Joo
authors.initials: KJ
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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