RESUMEN
1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 inhibitors resulting in the advancement of a clinical candidate.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores de Fosfodiesterasa 5 , Pirimidinas/química , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Relación Estructura-ActividadRESUMEN
1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.
Asunto(s)
Antihipertensivos/química , Inhibidores Enzimáticos/química , Inhibidores de Fosfodiesterasa 5 , Pirimidinas/química , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Inhibidores de Fosfodiesterasa 5 , Pirazinas/síntesis química , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Dominio Catalítico , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/química , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Estructura Terciaria de Proteína , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Antígenos de Neoplasias , Butiratos/química , Línea Celular , Humanos , Integrinas/antagonistas & inhibidores , Estructura Molecular , Oxadiazoles/química , Receptores de Vitronectina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.
Asunto(s)
Anticolesterolemiantes/síntesis química , Benzotiepinas/síntesis química , Ácidos y Sales Biliares/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Animales , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Benzotiepinas/química , Benzotiepinas/farmacología , Disponibilidad Biológica , Línea Celular , Cricetinae , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Mesocricetus , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido Taurocólico/metabolismoRESUMEN
In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.
Asunto(s)
Anticolesterolemiantes/síntesis química , Benzotiepinas/síntesis química , Ácidos y Sales Biliares/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Absorción , Animales , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , Benzotiepinas/química , Benzotiepinas/farmacocinética , Línea Celular , Cricetinae , Cristalización , Humanos , Humedad , Masculino , Mesocricetus , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Ácido Taurocólico/metabolismo , Difracción de Rayos XRESUMEN
A series of 5-aryl-3,3-dibutyl-7-(dimethylamino)-1,2-benzothiazepin-4-ol 1,1-dioxides were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT) for the potential treatment for hyperlipidemia. Several 1,2-benzothiazepines exhibited low nanomolar in vitro activity. The synthesis and initial in vitro potency data is presented for this novel class of compounds.
Asunto(s)
Hipolipemiantes/síntesis química , Hipolipemiantes/farmacología , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Tiazepinas/síntesis química , Tiazepinas/farmacología , Animales , Línea Celular , Cricetinae , Electrones , Humanos , Indicadores y Reactivos , Oxidación-Reducción , PolietilenglicolesRESUMEN
A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.