title: Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
abstract: Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
authors.affiliation: Department of Chemistry, Michigan Laboratories, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. jie.li1@bms.com
authors.forename: Jie Jack
authors.initials: JJ
authors.lastname: Li
authors.forename: Joe
authors.initials: J
authors.lastname: Nahra
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Amy
authors.initials: A
authors.lastname: Bunker
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Brien
authors.forename: Wen-Song
authors.initials: WS
authors.lastname: Yue
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Chiu-Fai
authors.initials: CF
authors.lastname: Man
authors.forename: Vijay
authors.initials: V
authors.lastname: Baragi
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kilgore
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dyer
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000188:drug therapy*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D052999:Quinazolinones