RESUMEN
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Enfermedades Metabólicas/tratamiento farmacológico , Sulfonamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Sitios de Unión , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéuticoRESUMEN
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Tetrazoles/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Ratones Transgénicos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Tetrazoles/farmacologíaRESUMEN
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 pyridyl amide/sulfonamide inhibitors of 11ß-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Piridinas/química , Pirimidinas/química , Triazoles/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed.
Asunto(s)
Ácidos/farmacología , Adamantano/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Ácido Acético/química , Ácido Acético/farmacología , Ácidos/química , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Unión Proteica , Relación Estructura-ActividadRESUMEN
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Animales , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Relación Estructura-ActividadRESUMEN
We report the synthesis and enzymatic evaluation of potent inhibitors of acetyl-CoA carboxylases (ACCs) containing biphenyl or 3-phenyl pyridine cores. These compounds inhibit both ACC1 and ACC2, or are moderately selective for either enzyme, depending on side chain substitution. Typical activities of the most potent compounds in this class are in the low double-digit to single-digit nanomolar range in in vitro assays using human ACC1 and ACC2 enzymes.
Asunto(s)
Fármacos Antiobesidad/química , Inhibidores Enzimáticos/química , Piridinas/química , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Piridinas/síntesis química , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta-hydroxysteroid dehydrogenase 1 inhibitors.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Piridinas/farmacología , Sulfonamidas/farmacología , Triazoles/farmacología , Humanos , Cinética , NADP/metabolismoRESUMEN
Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is a key enzyme in triacylglycerol synthesis, and inhibiting this enzyme is a promising approach for treating obesity, type II diabetes, and dyslipidemia. There are two distinct DGAT enzymes: DGAT1 and DGAT2. The conventional assay for measuring DGAT activity is a thin layer chromatography (TLC) method, which is not amenable to screening a large number of compounds. To increase the throughput, we have developed a novel, homogeneous scintillation proximity assay (SPA) for DGAT. In this assay, when (3)H-labeled acyl-CoA is used as the acyl donor and diacylglycerol is used as the acyl acceptor, the (3)H-labeled triacylglycerol product formed in the reaction binds to polylysine SPA beads, producing a signal that is measured in a TopCount or LEADseeker. The apparent Michaelis-Menten kinetic parameters determined by this DGAT SPA method agreed well with the values determined with the conventional TLC assay. The statistical values also indicate that the DGAT SPA is a robust assay, with a Z' of more than 0.60 and a signal/background ratio of approximately 9. These results suggest that the current assay provides high-throughput capacity for the identification of DGAT inhibitors.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/análisis , Animales , Bovinos , Diacilglicerol O-Acetiltransferasa/metabolismo , Dimetilsulfóxido/metabolismo , Enzimas Inmovilizadas/análisis , Enzimas Inmovilizadas/metabolismo , Cinética , Microesferas , Ratas , Reproducibilidad de los Resultados , Conteo por Cintilación , Sensibilidad y Especificidad , Albúmina Sérica Bovina/metabolismo , Triglicéridos/biosíntesisRESUMEN
The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.
Asunto(s)
Hormona del Crecimiento/metabolismo , Ácidos Pentanoicos/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Carbamatos/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Indoles/farmacología , Modelos Químicos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacología , Hormonas Peptídicas/química , Ratas , Compuestos de Espiro/farmacología , Estereoisomerismo , Tetrazoles/farmacologíaRESUMEN
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Hormona del Crecimiento/metabolismo , Tetrazoles/química , Amidas/química , Animales , Línea Celular , Glioma/metabolismo , Hormona del Crecimiento/sangre , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Benzoxazoles/química , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).
Asunto(s)
Diseño de Fármacos , Hormona del Crecimiento/metabolismo , Serina/análogos & derivados , Tetrazoles/química , Tetrazoles/farmacología , Animales , Carbamatos/farmacología , Estructura Molecular , Ratas , Serina/química , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Amidas/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
RESUMEN
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Músculo Esquelético/efectos de los fármacos , Próstata/efectos de los fármacos , Pirroles/síntesis química , Pirroles/farmacología , Receptores Androgénicos/metabolismo , Testosterona/análogos & derivados , Envejecimiento/metabolismo , Animales , Aromatasa/metabolismo , Unión Competitiva , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Dihidrotestosterona/química , Dihidrotestosterona/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Humanos , Imidazoles/metabolismo , Ligandos , Hormona Luteinizante/sangre , Masculino , Músculo Esquelético/fisiología , Orquiectomía , Próstata/fisiología , Estructura Terciaria de Proteína , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/química , Receptores Androgénicos/genética , Testosterona/química , Testosterona/metabolismo , Transcripción Genética/fisiologíaRESUMEN
Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicina/análogos & derivados , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Oxazoles/uso terapéutico , Receptores Activados del Proliferador del Peroxisoma/agonistas , Adiponectina/sangre , Animales , Glucemia/efectos de los fármacos , Corticosterona/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dieta , Femenino , Glicina/farmacología , Glicina/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Hígado , Ratones , Obesidad , Oxazoles/farmacología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Rosiglitazona , Tiazolidinedionas/uso terapéuticoRESUMEN
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Asunto(s)
Anabolizantes/síntesis química , Imidazoles/síntesis química , Músculo Esquelético/efectos de los fármacos , Pirroles/síntesis química , Receptores Androgénicos/metabolismo , Administración Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Semivida , Imidazoles/farmacocinética , Imidazoles/farmacología , Masculino , Modelos Moleculares , Músculo Esquelético/anatomía & histología , Orquiectomía , Próstata/anatomía & histología , Próstata/efectos de los fármacos , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Asunto(s)
Carbamatos/síntesis química , Hormona del Crecimiento/metabolismo , Tetrazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Ésteres , Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/metabolismo , Humanos , Macaca fascicularis , Ratas , Solubilidad , Relación Estructura-Actividad , Tetrazoles/farmacocinética , Tetrazoles/farmacología , AguaRESUMEN
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.