Discovery of hydroxy pyrimidine Factor IXa inhibitors

Charles L Jayne; Teresa Andreani; Tin-Yau Chan; Mariappan V Chelliah; Martin C Clasby; Michael Dwyer; Keith A Eagen; Steve Fried; William J Greenlee; Zhuyan Guo; Brian Hawes; Alan Hruza; Richard Ingram; Kartik M Keertikar; Santhosh Neelamkavil; Paul Reichert; Yan Xia; Samuel Chackalamannil

doi:10.1016/j.bmcl.2020.127279

Discovery of hydroxy pyrimidine Factor IXa inhibitors

Bioorg Med Chem Lett. 2020 Aug 1;30(15):127279. doi: 10.1016/j.bmcl.2020.127279. Epub 2020 May 23.

Authors

Charles L Jayne¹, Teresa Andreani², Tin-Yau Chan², Mariappan V Chelliah², Martin C Clasby², Michael Dwyer², Keith A Eagen², Steve Fried³, William J Greenlee², Zhuyan Guo², Brian Hawes³, Alan Hruza², Richard Ingram², Kartik M Keertikar², Santhosh Neelamkavil², Paul Reichert², Yan Xia², Samuel Chackalamannil²

Affiliations

¹ Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA. Electronic address: Charles.Jayne@merck.com.
² Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
³ Department of Biology, Merck & Co., Inc., Kenilworth, NJ 07033, USA.

PMID: 32527459
DOI: 10.1016/j.bmcl.2020.127279

Abstract

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

Keywords: Factor IXa; Factor IXa inhibition; Pyrimidine; Thrombosis.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Factor IXa / antagonists & inhibitors*
Factor IXa / metabolism
Factor Xa Inhibitors / chemical synthesis
Factor Xa Inhibitors / chemistry
Factor Xa Inhibitors / pharmacology*
Humans
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Factor Xa Inhibitors
Pyrimidines
Factor IXa