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Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors |
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| Authors: | Alexander Heim-Riether Steven J Taylor Shuang Liang Donghong Amy Gao Zhaoming Xiong E Michael August Brandon K Collins Bennett T Farmer II Kathleen Haverty Melissa Hill-Drzewi Hans-Dieter Junker S Mariana Margarit Neil Moss Thomas Neumann John R Proudfoot Lana Smith Keenan Renate Sekul Qiang Zhang Jun Li Neil A Farrow |
| Institution: | aBoehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Rd, Ridgefield, CT 06877, USA;bBoehringer Ingelheim Pharmaceuticals, Department of Immunology and Inflammation, 900 Ridgebury Rd, Ridgefield, CT 06877, USA;cGraffinity Pharmaceuticals GmbH, Im Neuenheimer Feld 518, 69120 Heidelberg, Germany |
| Abstract: | Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1′ pocket. |
| Keywords: | MMP-13 Non-Zn-chelating inhibitor SAR |
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