2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2014 Oct 1;22(19):5487-505. doi: 10.1016/j.bmc.2014.07.025.
Hiroshi Nara 1,  Kenjiro Sato 2,  Takako Naito 2,  Hideyuki Mototani 2,  Hideyuki Oki 2,  Yoshio Yamamoto 2,  Haruhiko Kuno 2,  Takashi Santou 2,  Naoyuki Kanzaki 2,  Jun Terauchi 2,  Osamu Uchikawa 2,  Masakuni Kori 2
Affiliations

Affiliations

  • 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.
PMID: 25192810 DOI: 10.1016/j.bmc.2014.07.025
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.

Figures
Products