Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase

Mark D Rosen; Craig R Woods; Steven D Goldberg; Michael D Hack; A Dawn Bounds; Young Yang; Pamela C Wagaman; Victor K Phuong; Angela P Ameriks; Terrance D Barrett; Kimon C Kanelakis; Jui Chang Chuang; Nigel P Shankley; Michael H Rabinowitz

doi:10.1016/j.bmcl.2009.10.033

Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6548-51. doi: 10.1016/j.bmcl.2009.10.033. Epub 2009 Oct 13.

Authors

Mark D Rosen¹, Craig R Woods, Steven D Goldberg, Michael D Hack, A Dawn Bounds, Young Yang, Pamela C Wagaman, Victor K Phuong, Angela P Ameriks, Terrance D Barrett, Kimon C Kanelakis, Jui Chang Chuang, Nigel P Shankley, Michael H Rabinowitz

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States. [email protected]

PMID: 19854648
DOI: 10.1016/j.bmcl.2009.10.033

Abstract

A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. The synthesis, structure-activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.

MeSH terms

Drug Discovery*
Heme / metabolism*
Indenes / chemical synthesis
Indenes / chemistry
Indenes / pharmacology*
Models, Molecular
Molecular Structure
Molecular Weight
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Stereoisomerism
Structure-Activity Relationship
eIF-2 Kinase / antagonists & inhibitors*
eIF-2 Kinase / metabolism

Substances

Indenes
Protein Kinase Inhibitors
Pyrazoles
Heme
eIF-2 Kinase