Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Zhong Lai; Shuwen He; Edward C Sherer; Zhicai Wu; Yang Yu; Richard Ball; Qingmei Hong; David X Yang; Liangqing Guo; Derun Li; Quang Tuang; Gary G Chicchi; Dorina Trusca; Kwei-Lan Tsao; Yun-Ping Zhou; Andrew D Howard; Ravi P Nargund; William K Hagmann

doi:10.1016/j.bmcl.2015.06.087

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3520-5. doi: 10.1016/j.bmcl.2015.06.087. Epub 2015 Jul 4.

Authors

Zhong Lai¹, Shuwen He², Edward C Sherer², Zhicai Wu², Yang Yu², Richard Ball², Qingmei Hong², David X Yang², Liangqing Guo², Derun Li², Quang Tuang², Gary G Chicchi³, Dorina Trusca³, Kwei-Lan Tsao³, Yun-Ping Zhou³, Andrew D Howard³, Ravi P Nargund², William K Hagmann²

Affiliations

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA. Electronic address: zhong_lai@merck.com.
² Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
³ Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.

PMID: 26199120
DOI: 10.1016/j.bmcl.2015.06.087

Abstract

We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.

Keywords: (4-Phenyl-1H-imidazol-2-yl)methanamine; Somatostatin receptor 3 (SSTR3) agonist; Structural overlay.

MeSH terms

Drug Discovery
Humans
Methylamines / chemistry*
Receptors, Somatostatin / chemistry*
Structure-Activity Relationship

Substances

Methylamines
Receptors, Somatostatin
somatostatin receptor 3
methylamine