RESUMEN
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Diseño de Fármacos , Propanoles/farmacología , Receptores de Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacología , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Receptores X del Hígado/agonistas , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Receptor X de Pregnano , Propanoles/síntesis química , Propanoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Receptor de Ácido Retinoico gammaRESUMEN
Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.
Asunto(s)
Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/metabolismo , Profármacos/síntesis química , Ticlopidina/análogos & derivados , Fenómenos Biológicos , Clopidogrel , Humanos , Microsomas Hepáticos/efectos de los fármacos , Piperidinas/química , Inhibidores de Agregación Plaquetaria/química , Profármacos/química , Estereoisomerismo , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/metabolismoRESUMEN
The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
Asunto(s)
Antitrombina III/farmacología , Benzofuranos/farmacología , Guanidinas/química , Lactamas/química , Administración Oral , Animales , Antitrombina III/química , Benzofuranos/química , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Perros , Haplorrinos , Humanos , Concentración 50 Inhibidora , Cinética , Lactamas/farmacología , Ligandos , Modelos Químicos , Ratas , Relación Estructura-Actividad , Tiourea/químicaRESUMEN
We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
Asunto(s)
Anticoagulantes/química , Inhibidores del Factor Xa , Guanidinas/química , Inhibidores de Serina Proteinasa/química , Anticoagulantes/farmacología , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Descubrimiento de Drogas , Guanidinas/farmacología , Humanos , Concentración 50 Inhibidora , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Inhibidores del Factor Xa , Indoles , Teoría Cuántica , Animales , Sitios de Unión/efectos de los fármacos , Simulación por Computador , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Factor Xa/efectos de los fármacos , Humanos , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Ratones , Modelos Químicos , Modelos Moleculares , Relación Estructura-Actividad , Análisis de Supervivencia , Ponzoñas/farmacología , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/enzimologíaRESUMEN
In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (32a) as a potent inhibitor of human Eg5 (ATPase IC50 104 nM) with good anti-proliferative activity in A2780 cells (IC50 234 nM).
Asunto(s)
Antineoplásicos/farmacología , Isoquinolinas/síntesis química , Cinesinas/antagonistas & inhibidores , Mitosis/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Adenosina Trifosfatasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Isoquinolinas/farmacología , Estructura Molecular , Tetrahidroisoquinolinas/síntesis química , Células Tumorales CultivadasRESUMEN
Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.
Asunto(s)
Cinesinas/antagonistas & inhibidores , Pirroles/síntesis química , Pirroles/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Pirroles/química , Relación Estructura-ActividadRESUMEN
Computer aided drug design led to a new class of spiro-barbiturates (e.g., 4a, MMP-13 K(i)=4.7 nM) that are potent inhibitors of MMP-13.
Asunto(s)
Barbitúricos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores de la Metaloproteinasa de la Matriz , Barbitúricos/farmacología , Simulación por Computador , Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Metaloproteinasa 13 de la Matriz , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
The preferred absolute configuration of two series of F(1)F(0)-ATP synthase inhibitors was determined. Although the configuration of the active enantiomer in each series is different, each series presents the same 'triaryl' pharmacophore to the enzyme binding site.
Asunto(s)
Mitocondrias/enzimología , ATPasas de Translocación de Protón/metabolismo , Sitios de Unión , Modelos Moleculares , EstereoisomerismoRESUMEN
N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
Asunto(s)
Etilenos/farmacología , Inhibidores del Factor Xa , Cetonas/farmacología , Lactamas/farmacología , Administración Oral , Etilenos/administración & dosificación , Etilenos/química , Humanos , Cetonas/administración & dosificación , Cetonas/química , Lactamas/administración & dosificación , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease.