Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere.

Downey JD, Saleh SA, Bridges TM, Morrison RD, Daniels JS, Lindsley CW, Breyer RM
Bioorg Med Chem Lett. 2013 23 (1): 37-41

PMID: 23218714 · PMCID: PMC3534858 · DOI:10.1016/j.bmcl.2012.11.046

Recent preclinical studies demonstrate a role for the prostaglandin E(2) (PGE(2)) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE(2) subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Animals Diabetes Mellitus Half-Life Humans Hypertension Mice Microsomes, Liver Pyridines Receptors, Prostaglandin E, EP1 Subtype Receptors, Prostaglandin E, EP3 Subtype Receptors, Thromboxane Structure-Activity Relationship Sulfonamides

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