Rapid development of two factor IXa inhibitors from hit to lead

Dann L Parker Jr; Shawn Walsh; Bing Li; Esther Kim; Aurash Sharipour; Cameron Smith; Yi-Heng Chen; Richard Berger; Bart Harper; Ting Zhang; Min Park; Min Shu; Jane Wu; Jiayi Xu; Sunita Dewnani; Edward C Sherer; Alan Hruza; Paul Reichert; Wayne Geissler; Lisa Sonatore; Kenneth Ellsworth; James Balkovec; William Greenlee; Harold B Wood

doi:10.1016/j.bmcl.2015.04.025

Rapid development of two factor IXa inhibitors from hit to lead

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2321-5. doi: 10.1016/j.bmcl.2015.04.025. Epub 2015 Apr 13.

Authors

Dann L Parker Jr¹, Shawn Walsh², Bing Li², Esther Kim², Aurash Sharipour², Cameron Smith², Yi-Heng Chen², Richard Berger², Bart Harper², Ting Zhang², Min Park², Min Shu², Jane Wu², Jiayi Xu², Sunita Dewnani², Edward C Sherer³, Alan Hruza⁴, Paul Reichert⁴, Wayne Geissler⁵, Lisa Sonatore⁵, Kenneth Ellsworth⁵, James Balkovec², William Greenlee², Harold B Wood²

Affiliations

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA. Electronic address: dann_parker@merck.com.
² Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
³ Department of Chemistry Modeling and Informatics, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
⁴ Department of Structural Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
⁵ Department of Pharmacology, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.

PMID: 25937013
DOI: 10.1016/j.bmcl.2015.04.025

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.

Keywords: Anticoagulant; Factor IXa; Hit-to-lead; Parallel synthesis; Structure based drug design.

MeSH terms

Anticoagulants / chemistry*
Anticoagulants / pharmacology*
Binding Sites
Drug Discovery
Factor IXa / antagonists & inhibitors*
Humans
Models, Molecular
Molecular Structure
Protein Conformation

Substances

Anticoagulants
Factor IXa