Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents

Paul S Humphries; Ross Bersot; John Kincaid; Eric Mabery; Kerryn McCluskie; Timothy Park; Travis Renner; Erin Riegler; Tod Steinfeld; Eric D Turtle; Zhi-Liang Wei; Erik Willis

doi:10.1016/j.bmcl.2017.12.051

Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents

Bioorg Med Chem Lett. 2018 Feb 1;28(3):293-297. doi: 10.1016/j.bmcl.2017.12.051. Epub 2017 Dec 24.

Authors

Affiliations

¹ Reset Therapeutics, 260 Littlefield Avenue, Suite 200, South San Francisco, CA 94080, USA. Electronic address: [email protected].
² Reset Therapeutics, 260 Littlefield Avenue, Suite 200, South San Francisco, CA 94080, USA.
³ Synterys, 29540 Kohoutek Way, Union City, CA 94587, USA.

PMID: 29292223
DOI: 10.1016/j.bmcl.2017.12.051

Abstract

A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.

Keywords: Carbazole; Circadian; Cryptochrome; Diabetes; SAR.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Carbazoles / chemistry
Carbazoles / pharmacology*
Cryptochromes / metabolism*
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Experimental / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Male
Mice
Molecular Structure
Obesity / drug therapy
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Amides
Carbazoles
Cryptochromes
Hypoglycemic Agents
carbazole
Urea