RESUMO
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.
Assuntos
Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Fármacos Dermatológicos/síntese química , Ácidos Hidroxâmicos/síntese química , Metaloendopeptidases/antagonistas & inibidores , Oxidiazóis/síntese química , Administração Cutânea , Proteína Morfogenética Óssea 1 , Cicatriz Hipertrófica/prevenção & controle , Colágeno/metabolismo , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Hidrólise , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Queloide/prevenção & controle , Inibidores de Metaloproteinases de Matriz , Oxidiazóis/química , Oxidiazóis/farmacologia , Permeabilidade , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.