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: Jie Jack Li, Joe Nahra, Adam R Johnson, Amy Bunker, Patrick O'Brien, Wen-Song Yue, Daniel F Ortwine, Chiu-Fai Man, Vijay Baragi, Kenneth Kilgore, Richard D Dyer, Hyo-Kyung Han
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 4 Pg. 835-41 (Feb 28 2008) ISSN: 0022-2623 [Print] United States
• PMID: 18251495 (Publication Type: Journal Article)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Pyridines
• Pyrimidines
• Quinazolinones

Topics

• Administration, Oral
• Animals
• Biological Availability
• Male
• Matrix Metalloproteinase Inhibitors
• Osteoarthritis (drug therapy)
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
• Quinazolinones (chemical synthesis, pharmacokinetics, pharmacology)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship