RESUMEN
BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Actinas/antagonistas & inhibidores , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacología , Administración Oral , Animales , Azetidinas/administración & dosificación , Azetidinas/química , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Femenino , Semivida , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Concentración 50 Inhibidora , Macaca fascicularis , Masculino , Ratones Obesos , Ratas , Relación Estructura-ActividadRESUMEN
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Asunto(s)
Antígeno-1 Asociado a Función de Linfocito/metabolismo , Compuestos de Espiro/síntesis química , Tiofenos/síntesis química , Animales , Adhesión Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Rechazo de Injerto/prevención & control , Humanos , Antígeno-1 Asociado a Función de Linfocito/química , Ratones , Modelos Moleculares , Estructura Molecular , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología , Trasplante HomólogoRESUMEN
BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
RESUMEN
[formula: see text] 3-Cyano epothilones 15-18 are the only examples of non-hydroxy C-3-substituted analogues. Their tubulin binding affinity and cytotoxicity provide meaningful structure-activity relationship information on the dependence of C-1/C-3 conformation upon activity. 12-Cyano epothilone 24 has improved pH stability over epothilone B, and its activity further supports the hypothesis that C-12 stereochemistry is not critical for tubulin affinity.
Asunto(s)
Epotilonas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Estabilidad de Medicamentos , Epotilonas/química , Epotilonas/farmacología , Humanos , Concentración de Iones de Hidrógeno , Estructura Molecular , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.