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Bioorg Med Chem. 2014 Oct 1;22(19):5487-505. doi: 10.1016/j.bmc.2014.07.025. Epub 2014 Aug 7.

Thieno[2,3-d]pyrimidine-2-carboxamides bearing a carboxybenzene group at 5-position: highly potent, selective, and orally available MMP-13 inhibitors interacting with the S1″ binding site.

Author information

1
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: hiroshi.nara@takeda.com.
2
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Abstract

On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1″ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.

KEYWORDS:

MMP-13; Matrix metalloproteinase; OA; Osteoarthritis; Structure-based drug design; Thieno[2,3-d]pyrimidin-4-one; X-ray crystallography

PMID:
25192810
DOI:
10.1016/j.bmc.2014.07.025
[Indexed for MEDLINE]

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