RESUMEN
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/metabolismo , Compuestos Heterocíclicos/farmacología , Receptores CXCR3/antagonistas & inhibidores , Amidas/administración & dosificación , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Humanos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirrolidinas/química , Tartratos/química , Proteína ADAM17 , Amidas/síntesis química , Amidas/química , Animales , Disponibilidad Biológica , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , RatasRESUMEN
The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM.
Asunto(s)
Piperazinas/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Receptores CXCR3/agonistas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piperazina , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Antiinflamatorios/química , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de Proteasas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Perros , Haplorrinos , Humanos , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , RatasRESUMEN
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteína ADAM17 , Animales , Ratas , Relación Estructura-ActividadRESUMEN
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hidantoínas/farmacología , Proteína ADAM17 , Inhibidores Enzimáticos/química , Hidantoínas/química , Enlace de Hidrógeno , Modelos Moleculares , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Asunto(s)
Receptor Cannabinoide CB2/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonas/química , Sulfonas/síntesis química , Animales , Canales de Calcio/metabolismo , Sistema Enzimático del Citocromo P-450 , Agonismo Inverso de Drogas , Humanos , Piperidinas/química , Ratas , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/farmacocinéticaRESUMEN
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.