Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative <b>1</b> and triazole derivative <b>2</b> with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, <b>31f</b> exhibited excellent potency for MMP-13 (IC₅₀ = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition

Discovery of 5‑Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α_1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities

A novel structural class of iminopyridine derivative <b>1</b> was identified as a potent and selective human α_1D adrenoceptor (α_1D adrenergic receptor; α_1D-AR) antagonist against α_1A- and α_1B-AR through screening of an in-house compound library. From initial structure–activity relationship studies, we found lead compound <b>9m</b> with hERG K⁺ channel liability. To develop analogues with reduced hERG K⁺ channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (<i>R</i>)-<b>9s</b> and <b>9u</b>, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, <b>9u</b> was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α_1D-AR antagonists and evaluate their effects in vivo