RESUMEN
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.
RESUMEN
Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.
RESUMEN
Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.
Asunto(s)
Aminas/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Descubrimiento de Drogas , Aminas/síntesis química , Aminas/química , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Transgénicos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
Asunto(s)
Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Bencilaminas/síntesis química , Bencilaminas/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Animales , Anticolesterolemiantes/farmacocinética , Aterosclerosis/tratamiento farmacológico , Benzamidas/farmacocinética , Bencilaminas/farmacocinética , Presión Sanguínea/efectos de los fármacos , Línea Celular , Colesterol/metabolismo , HDL-Colesterol/sangre , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Perros , Descubrimiento de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Quinolinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
A series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein with aminoheterocycles appended onto the N-terminus of the chemotype were explored as urea mimetics. Potent compounds were discovered and were further optimized to improve metabolic stability and PXR transactivation profile.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Biomimética , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Estabilidad de Medicamentos , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Compuestos Heterocíclicos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Relación Estructura-Actividad , Urea/químicaRESUMEN
A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described. Optimization of the urea moiety, particularly by incorporation of fluorine, is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Urea/análogos & derivados , Urea/farmacología , Aminas/sangre , Aminas/química , Aminas/metabolismo , Aminas/farmacología , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Halogenación , Humanos , Ratones , Piridinas/sangre , Piridinas/metabolismo , Ratas , Urea/sangre , Urea/metabolismoRESUMEN
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
Asunto(s)
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Estilbenos/química , Estilbenos/farmacología , Animales , Anticolesterolemiantes/síntesis química , Apolipoproteína B-100/antagonistas & inhibidores , Apolipoproteína B-100/metabolismo , Presión Sanguínea/efectos de los fármacos , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Enfermedad Coronaria/tratamiento farmacológico , Cricetinae , Descubrimiento de Drogas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Transgénicos , Estructura Molecular , Piridinas/síntesis química , Ratas , Estilbenos/síntesis químicaRESUMEN
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.