RESUMEN
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Cinamatos/síntesis química , Cinamatos/farmacología , Higromicina B/análogos & derivados , Higromicina B/síntesis química , Higromicina B/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Pirimidinas/química , Pirrolidinas/química , Compuestos de Espiro/química , Animales , Estabilidad de Enzimas/efectos de los fármacos , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de Proteasas/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Ratas , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirimidinonas/química , Animales , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Peso Molecular , Ratas , Sales (Química)/química , Sodio/química , Relación Estructura-ActividadRESUMEN
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.
Asunto(s)
Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 3 de la Matriz/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Colagenasas/química , Indicadores y Reactivos , Isomerismo , Metaloproteinasa 1 de la Matriz/química , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 3 de la Matriz/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.