Discovery of a series of potent arylthiadiazole H(3) antagonists

Dong Xiao; Anandan Palani; Michael Sofolarides; Ying Huang; Robert Aslanian; Henry Vaccaro; Liwu Hong; Brian McKittrick; Robert E West Jr; Shirley M Williams; Ren-Long Wu; Joyce Hwa; Christopher Sondey; Jean Lachowicz

doi:10.1016/j.bmcl.2010.11.065

Discovery of a series of potent arylthiadiazole H(3) antagonists

Bioorg Med Chem Lett. 2011 Jan 15;21(2):861-4. doi: 10.1016/j.bmcl.2010.11.065. Epub 2010 Nov 21.

Authors

Dong Xiao¹, Anandan Palani, Michael Sofolarides, Ying Huang, Robert Aslanian, Henry Vaccaro, Liwu Hong, Brian McKittrick, Robert E West Jr, Shirley M Williams, Ren-Long Wu, Joyce Hwa, Christopher Sondey, Jean Lachowicz

Affiliation

¹ Chemical Research Department, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. dong.xiao@merck.com

PMID: 21186123
DOI: 10.1016/j.bmcl.2010.11.065

Abstract

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.

MeSH terms

Animals
Brain / metabolism
Histamine Antagonists / chemistry*
Histamine Antagonists / pharmacokinetics
Histamine Antagonists / pharmacology*
Humans
Mice
Rats
Receptors, Histamine H3 / metabolism*
Structure-Activity Relationship
Thiadiazoles / chemistry*
Thiadiazoles / pharmacokinetics
Thiadiazoles / pharmacology*

Substances

Histamine Antagonists
Receptors, Histamine H3
Thiadiazoles