3WV1

Crystal structure of the catalytic domain of MMP-13 complexed with 4-(2-((6-fluoro-2-((3-methoxybenzyl)carbamoyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid

Summary for 3WV1

• Entry DOI: 10.2210/pdb3wv1/pdb
• Related: 3WV2 3WV3
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: mmp-13, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P45452
• Total number of polymer chains: 2
• Total formula weight: 40013.68

Authors

Oki, H.,Tanaka, Y. (deposition date: 2014-05-12, release date: 2015-05-20, Last modification date: 2024-03-20)

Primary citation

Nara, H.,Sato, K.,Naito, T.,Mototani, H.,Oki, H.,Yamamoto, Y.,Kuno, H.,Santou, T.,Kanzaki, N.,Terauchi, J.,Uchikawa, O.,Kori, M.
Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach
J.Med.Chem., 57:8886-8902, 2014

PubMed Abstract: Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

PubMed: 25264600
DOI: 10.1021/jm500981k

Experimental method

X-RAY DIFFRACTION (1.98 Å)