RESUMEN
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.
Asunto(s)
Lactamas/síntesis química , Lactamas/farmacología , Prostaglandinas E Sintéticas/síntesis química , Prostaglandinas E Sintéticas/farmacología , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Administración Tópica , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Cricetinae , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Dinoprostona/química , Evaluación Preclínica de Medicamentos/métodos , Curación de Fractura/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Lactamas/administración & dosificación , Masculino , Ratones , Microesferas , Estructura Molecular , Poliglactina 910/administración & dosificación , Poliglactina 910/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazolidinas/químicaRESUMEN
To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.