Synthesis and evaluation of a potent, well-balanced EP2/EP3 dual agonist.

Abstract

A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.

• Authors: Akihiro Kinoshita, Masato Higashino, Koji Yoshida, Yoshiyuki Aratani, Akito Kakuuchi, Keisuke Hanada, Hiroyuki Takeda, Atsushi Naganawa, Hidekazu Matsuya, Kazuyuki Ohmoto
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 1 Pg. 200-214 (01 01 2018) ISSN: 1464-3391 [Electronic] England
• PMID: 29203142 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• ONO-8055
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP3 Subtype
• Thiazoles

Topics

• Animals
• Caco-2 Cells
• Cell Membrane Permeability (drug effects)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Haplorhini
• Humans
• Male
• Models, Molecular
• Molecular Structure
• Rats
• Receptors, Prostaglandin E, EP2 Subtype (agonists)
• Receptors, Prostaglandin E, EP3 Subtype (agonists)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)