Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors

Zilun Hu; Cailan Wang; Wei Han; Karen A Rossi; Jeffrey M Bozarth; Yiming Wu; Steven Sheriff; Joseph E Myers Jr; Joseph M Luettgen; Dietmar A Seiffert; Ruth R Wexler; Mimi L Quan

doi:10.1016/j.bmcl.2018.02.049

Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors

Bioorg Med Chem Lett. 2018 Apr 1;28(6):987-992. doi: 10.1016/j.bmcl.2018.02.049. Epub 2018 Feb 27.

Authors

Affiliations

¹ Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States. Electronic address: [email protected].
² Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States.
³ Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Road, Pennington, NJ 08543, United States.
⁴ Bristol-Myers Squibb Company, Research and Development, US Rt. 206 & Province Line Road, Princeton, NJ 08540, United States.

PMID: 29501396
DOI: 10.1016/j.bmcl.2018.02.049

Abstract

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.

Keywords: FXIa; Factor XIa inhibitors; Pyridazine; Pyridazinone; Thrombosis.

MeSH terms

Crystallography, X-Ray
Dose-Response Relationship, Drug
Factor XIa / antagonists & inhibitors*
Factor XIa / metabolism
Humans
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Pyridazines
Serine Proteinase Inhibitors
Factor XIa