title: 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.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nara
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sato
authors.forename: Takako
authors.initials: T
authors.lastname: Naito
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mototani
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kuno
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchikawa
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000595646:4-(2-((6-fluoro-2-((((3-(methyloxy)phenyl)methyl)amino)carbonyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid; D001565:Benzoates; D061965:Matrix Metalloproteinase Inhibitors; D011799:Quinazolines; D053509:Matrix Metalloproteinase 13