Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists

Qingbei Zeng; Stuart B Rosenblum; Zhaoxia Yang; Yueheng Jiang; Kevin D McCormick; Robert G Aslanian; Luli Duguma; Joseph A Kozlowski; Neng-Yang Shih; John A Hey; Robert E West Jr; Walter A Korfmacher; Michael Berlin; Christopher W Boyce

doi:10.1016/j.bmcl.2013.08.012

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists

Bioorg Med Chem Lett. 2013 Nov 1;23(21):6001-3. doi: 10.1016/j.bmcl.2013.08.012. Epub 2013 Aug 13.

Authors

Qingbei Zeng¹, Stuart B Rosenblum, Zhaoxia Yang, Yueheng Jiang, Kevin D McCormick, Robert G Aslanian, Luli Duguma, Joseph A Kozlowski, Neng-Yang Shih, John A Hey, Robert E West Jr, Walter A Korfmacher, Michael Berlin, Christopher W Boyce

Affiliation

¹ Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.

PMID: 24050887
DOI: 10.1016/j.bmcl.2013.08.012

Abstract

A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.

Keywords: Benzimidazolone; H(3)-antagonists; P450 inhibition.

MeSH terms

Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
Cytochrome P-450 Enzyme System / metabolism
Guinea Pigs
Histamine H3 Antagonists / chemical synthesis
Histamine H3 Antagonists / chemistry*
Histamine H3 Antagonists / pharmacokinetics
Histamine H3 Antagonists / pharmacology*
Humans
Rats
Receptors, Histamine H3 / metabolism
Structure-Activity Relationship

Substances

Benzimidazoles
Histamine H3 Antagonists
Receptors, Histamine H3
benzimidazolone
Cytochrome P-450 Enzyme System