Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors. Issue 23 (1st December 2016)

• Record Type: Journal Article
• Authors: Nara, Hiroshi; Sato, Kenjiro; Kaieda, Akira; Oki, Hideyuki; Kuno, Haruhiko; Santou, Takashi; Kanzaki, Naoyuki; Terauchi, Jun; Uchikawa, Osamu; Kori, Masakuni
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 23(2016)
• Page Start: 6149
• Page End: 6165
• Publication Date: 2016-12-01
• Subjects: Matrix metalloproteinase -- MMP-13 -- Fused pyrimidine-2-carboxamide -- Zinc-binding group -- Structure-based drug design -- Osteoarthritis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.09.009
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound1 . We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor35 exhibited excellent potency (IC50 = 0.071 nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.