RESUMEN
Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.
Asunto(s)
Ácido Aspártico/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inhibidores de Proteasas/química , Renina/antagonistas & inhibidores , Ácido Aspártico/química , Sitios de Unión , Cristalografía por Rayos X , Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Inhibidores de Proteasas/metabolismo , Unión Proteica , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.
Asunto(s)
Azepinas/química , Catepsinas/antagonistas & inhibidores , Niacinamida/análogos & derivados , Inhibidores de Proteasas/química , Alanina/química , Azepinas/síntesis química , Azepinas/farmacología , Sitios de Unión , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Catepsina L/antagonistas & inhibidores , Catepsina L/metabolismo , Catepsinas/metabolismo , Simulación por Computador , Humanos , Niacinamida/síntesis química , Niacinamida/química , Niacinamida/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
Asunto(s)
Azepinas/síntesis química , Conservadores de la Densidad Ósea/síntesis química , Catepsinas/antagonistas & inhibidores , Sulfonas/síntesis química , Animales , Azepinas/química , Azepinas/farmacología , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacología , Catepsina K , Catepsinas/química , Línea Celular , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Haplorrinos , Humanos , Conformación Molecular , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.
Asunto(s)
Azepinas/síntesis química , Catepsinas/antagonistas & inhibidores , Catepsinas/química , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/síntesis química , Sulfonas/síntesis química , Amidas/química , Azepinas/química , Sitios de Unión , Catepsina L , Inhibidores de Cisteína Proteinasa/química , Humanos , Modelos Moleculares , Quinolinas/química , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Triazoles/síntesis química , Aminopeptidasas/química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cobalto/metabolismo , Colágeno , Cristalografía por Rayos X , Combinación de Medicamentos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Activación Enzimática , Humanos , Laminina , Metaloendopeptidasas/química , Ratones , Modelos Moleculares , Estructura Molecular , Proteoglicanos , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.