Synthesis and evaluation of γ-lactam analogs of PGE₂ as EP4 and EP2/EP4 agonists.

Abstract

To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.

• Authors: Tohru Kambe, Toru Maruyama, Yoshihiko Nakai, Hiroji Oida, Takayuki Maruyama, Nobutaka Abe, Akio Nishiura, Hisao Nakai, Masaaki Toda
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 11 Pg. 3502-22 (Jun 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22546206 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• 2-mercaptothiazole-4-carboxylic acid
• Delayed-Action Preparations
• Lactams
• Prostaglandins E, Synthetic
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Thiazolidines
• Polyglactin 910
• Dinoprostone

Topics

• Administration, Topical
• Animals
• Blood Pressure (drug effects)
• CHO Cells
• Cricetinae
• Delayed-Action Preparations (administration & dosage, chemistry)
• Dinoprostone (chemistry)
• Drug Evaluation, Preclinical (methods)
• Fracture Healing (drug effects)
• Heart Rate (drug effects)
• Lactams (administration & dosage, chemical synthesis, pharmacology)
• Male
• Mice
• Microspheres
• Molecular Structure
• Polyglactin 910 (administration & dosage, chemistry)
• Prostaglandins E, Synthetic (chemical synthesis, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Prostaglandin E, EP2 Subtype (agonists)
• Receptors, Prostaglandin E, EP4 Subtype (agonists)
• Structure-Activity Relationship
• Thiazolidines (chemistry)