Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

Sue Cramp; Hazel J Dyke; Christopher Higgs; David E Clark; Matthew Gill; Pascal Savy; Neil Jennings; Steve Price; Peter M Lockey; Dennis Norman; Soraya Porres; Francis Wilson; Alison Jones; Nigel Ramsden; Raffaella Mangano; Dan Leggate; Marie Andersson; Richard Hale

doi:10.1016/j.bmcl.2010.02.097

Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2516-9. doi: 10.1016/j.bmcl.2010.02.097. Epub 2010 Mar 3.

Authors

Sue Cramp¹, Hazel J Dyke, Christopher Higgs, David E Clark, Matthew Gill, Pascal Savy, Neil Jennings, Steve Price, Peter M Lockey, Dennis Norman, Soraya Porres, Francis Wilson, Alison Jones, Nigel Ramsden, Raffaella Mangano, Dan Leggate, Marie Andersson, Richard Hale

Affiliation

¹ Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex, UK. [email protected]

PMID: 20299215
DOI: 10.1016/j.bmcl.2010.02.097

Abstract

The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H(4) receptor inverse agonists is described. The initial hit, 3A (IC(50) 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC(50) 1 nM) as well as enhanced microsomal stability.

MeSH terms

Animals
Biological Availability
Drug Discovery
Histamine Antagonists / chemistry
Histamine Antagonists / pharmacokinetics
Histamine Antagonists / pharmacology*
Inhibitory Concentration 50
Macaca fascicularis
Rats
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, Histamine
Receptors, Histamine H4
Stereoisomerism

Substances

Histamine Antagonists
Hrh4 protein, rat
Receptors, G-Protein-Coupled
Receptors, Histamine
Receptors, Histamine H4