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Rapid development of two factor IXa inhibitors from hit to lead
Dann L Parker1, Shawn Walsh1, Bing Li1
1Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Abstract:
Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.
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