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.

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm701274vDOI Listing

Publication Analysis

Top Keywords

quinazolinones pyrido[34-d]pyrimidin-4-ones
8
pyrido[34-d]pyrimidin-4-ones orally
8
orally active
8
active specific
8
specific matrix
8
matrix metalloproteinase-13
8
metalloproteinase-13 inhibitors
8
treatment osteoarthritis
8
inhibitors treatment
4
osteoarthritis quinazolinones
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!