RESUMEN
Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic beta-dicarbonyl. This design concept for leaving groups has not been previously reported. A structure-activity relationship has been developed and the concept extended to several types of alicyclic and heterocyclic beta-dicarbonyl systems. This work led to the identification of a potent (K*i of 0.066 nM) and tissue stable (in vitro: blood t1/2 = 160 min, liver t1/2 > 240 min) benzisothiazolone HLE inhibitor, WIN 65936 (13b).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Elastasa Pancreática/antagonistas & inhibidores , Sacarina/análogos & derivados , Estabilidad de Medicamentos , Inhibidores Enzimáticos/farmacología , Semivida , Humanos , Elastasa de Leucocito , Hígado/metabolismo , Sustancias Macromoleculares , Espectroscopía de Resonancia Magnética , Estructura Molecular , Sacarina/síntesis química , Sacarina/farmacocinética , Sacarina/farmacología , Relación Estructura-ActividadRESUMEN
Human leukocyte elastase (HLE) has been proposed as a primary mediator of pulmonary emphysema and other inflammatory airway diseases. HLE is capable of cleaving many proteins, including elastin, other components of connective tissue, certain complement proteins, and receptors. Under normal conditions an appropriate balance exists in the lung between HLE and endogenous inhibitors, which scavenge the released enzyme before it exerts deleterious effects in the lung. Emphysema is thought to result from an imbalance in the lung between HLE and endogenous inhibitor (elevated elastase or insufficient inhibitor) that leads to the destruction of alveoli. We have identified WIN 64733 (2) and WIN 63759 (3) as potent (Ki* = 14 and 13 pM, respectively), selective, mechanism-based inhibitors of HLE which are orally bioavailable in the dog (absolute bioavailability 46% and 21%, respectively). In this series the in vitro stabilities of the inhibitors in blood, jejunal homogenates, and liver S9 homogenates are useful predictors of oral bioavailability. After being administered orally (30 mg/kg) to dogs, compounds 2 and 3 are found in the lung, being detected in the epithelial lining fluid obtained by bronchoalveolar lavage (Cmax of 2.5 and 0.47 microgram/mL, respectively).
Asunto(s)
Elastasa Pancreática/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Clorobenzoatos/síntesis química , Clorobenzoatos/farmacocinética , Clorobenzoatos/farmacología , Cricetinae , Perros , Estabilidad de Medicamentos , Humanos , Técnicas In Vitro , Elastasa de Leucocito , Pulmón/enzimología , Pulmón/metabolismo , Macaca fascicularis , Mesocricetus , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinéticaAsunto(s)
Ácidos Carboxílicos/síntesis química , Elastasa Pancreática/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Tiazoles/síntesis química , Tiazoles/farmacología , Ácidos Carboxílicos/farmacología , Humanos , Cinética , Elastasa de Leucocito , Estructura Molecular , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
A combination of structure-based design and both solution, and solid-phase synthesis were utilized to derive a potent (nM) series of HIV-1 protease inhibitors bearing a structurally novel backbone. Detailed structural analysis of several inhibitors prepared in this series has suggested that rigidification of the P1/P2 region of this class of molecules may result in compounds with improved potency.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Cristalografía por Rayos X , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A set of HIV protease inhibitors represented by compound 2 has previously been described. Structural and conformational analysis of this compound suggested that conformational restriction of the P1/P2 portion of the molecule could lead to a novel set of potent protease inhibitors. Thus, probe compounds 3-7 were designed, synthesized, and found to be potent inhibitors of HIV protease.