Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
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.
Li
Jie Jack
JJ
Department of Chemistry, Michigan Laboratories, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. jie.li1@bms.com
Nahra
Joe
J
Johnson
Adam R
AR
Bunker
Amy
A
O'Brien
Patrick
P
Yue
Wen-Song
WS
Ortwine
Daniel F
DF
Man
Chiu-Fai
CF
Baragi
Vijay
V
Kilgore
Kenneth
K
Dyer
Richard D
RD
Han
Hyo-Kyung
HK
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
D061965:Matrix Metalloproteinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D052999:Quinazolinones