Publications by authors named "Chiu-Fai Man"

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

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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.

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Article Synopsis
  • MMP13 is a zinc-dependent protease responsible for breaking down type II collagen in cartilage, making it a key target in treating osteoarthritis.
  • Previous MMP inhibitors caused painful musculoskeletal side effects due to their non-selectivity, but new inhibitors developed by researchers are designed to selectively target MMP13 without affecting other proteins.
  • These new MMP13 inhibitors have shown promise in reducing cartilage damage in animal models without causing negative side effects, potentially leading to safer and more effective osteoarthritis treatments.
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