Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration.

Authors :: Sparks SM
Spearing PK
Diaz CJ
Cowan DJ
Jayawickreme C
Chen G
Rimele TJ
Generaux C
Harston LT
Roller SG
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Oct 15; Vol. 27 (20), pp. 4673-4677. Date of Electronic Publication: 2017 Sep 07.
Publication Year :: 2017
Abstract: Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Subjects :: Animals
Calcium metabolism
Cell Membrane Permeability drug effects
Dogs
Gastrointestinal Tract metabolism
HEK293 Cells
Humans
Madin Darby Canine Kidney Cells
Pyrrolidines chemistry
Pyrrolidines metabolism
Pyrrolidines pharmacology
Receptors, Calcium-Sensing genetics
Receptors, Calcium-Sensing metabolism
Structure-Activity Relationship
Receptors, Calcium-Sensing agonists

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