- 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
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On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 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, 31f 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.
- Nara, Hiroshi,Kaieda, Akira,Sato, Kenjiro,Naito, Takako,Mototani, Hideyuki,Oki, Hideyuki,Yamamoto, Yoshio,Kuno, Haruhiko,Santou, Takashi,Kanzaki, Naoyuki,Terauchi, Jun,Uchikawa, Osamu,Kori, Masakuni
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p. 608 - 626
(2017/02/05)
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- Novel 4-oxothienopyrimidinyl propanoic acid derivatives as AMPactivated protein kinase (AMPK) activators
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Adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK) is a highly conserved sensor of cellular energy. AMPK has been recognized as a key regulator of mammalian metabolic function and has emerged as an attractive target for the treatment of meta
- Sasmal, Pradip K.,Jaleel, Mahaboobi,Rao, P. Tirumala,Munikumar,Bhattacharya, Megha,Kumar, Nutakki Ravi,Neelima, Poondla,Rawoof, Khaji Abdul,Rao, P. Narasimha,Abbineni, Chandrasekhar,Roshaiah,Sridhar,Kumar, Thammera Ranjith,Vinu, Menon C.A.,Potluri, Vijay,Misra, Parimal,Talwar, Rashmi,Das, Saibal Kumar
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p. 778 - 785
(2014/07/07)
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- HETEROCYCLIC AMIDE COMPOUND AND USE THEREOF
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The present invention provides a novel amide compound represented by the following formula, which has a matrix metalloproteinase inhibitory activity and is useful as a pharmaceutical agent. wherein each symbol is as defined in the specification.
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Page/Page column 141
(2008/12/07)
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- Pharmaceutically active compounds and methods of use
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New fused thiophene compounds are provided and methods of using those compounds for a variety of therapeutic indications. Compounds of the invention are particularly useful for treatment of neuropathic pain.
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