RESUMO
The microsomal prostaglandin E2 synthase 1 (mPGES-1) became a desirable target in recent years for the research of new anti-inflammatory drugs. Even though many potent inhibitors of human mPGES-1, tested in vitro assay systems, have been synthesized, they all failed in preclinical trials in rodent models of inflammation, due to the lack of activity on rodent enzyme. Within this work we want to present a new class of mPGES-1 inhibitors derived from a benzenesulfonamide scaffold with inhibitory potency on human and murine mPGES-1. Starting point with an IC50 of 13.8 µM on human mPGES-1 was compound 1 (4-{benzyl[(4-methoxyphenyl)methyl]sulfamoyl}benzoic acid; FR4), which was discovered by a virtual screening approach. Optimization during a structure-activity relationship (SAR) process leads to compound 28 (4-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]sulfamoyl]benzoic acid) with an improved IC50 of 0.8 µM on human mPGES-1. For the most promising compounds a broad pharmacological characterization has been carried out to estimate their anti-inflammatory potential.
Assuntos
Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Oxirredutases Intramoleculares/metabolismo , Ligantes , Camundongos , Estrutura Molecular , Células NIH 3T3 , Prostaglandina-E Sintases , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Dual inhibition of microsomal prostaglandin E(2) synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC(50) mPGES-1=0.94 µM; IC(50) 5-LO=0.1 µM) showing the most favorable in vitro pharmacological profile.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Araquidonato 5-Lipoxigenase/química , Oxirredutases Intramoleculares/química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/síntese química , Naftóis/química , Pirimidinas/química , Anti-Inflamatórios/farmacologia , Concentração Inibidora 50 , Oxirredutases Intramoleculares/antagonistas & inibidores , Inibidores de Lipoxigenase/farmacologia , Modelos Biológicos , Estrutura Molecular , Prostaglandina-E Sintases , Relação Estrutura-AtividadeRESUMO
Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in glucose and lipid homeostasis. PPARgamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARgamma modulators (SPPARgammaMs) was developed, which are believed to show less side effects than full PPARgamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPARalpha and PPARgamma, leads to low micromolar active balanced dual agonists of PPARalpha and PPARgamma. Herein we present modifications of pirinixic acid leading to subtype-selective PPARgamma agonists and furthermore the development of a selective PPARgamma modulator guided by molecular docking studies.