RESUMEN

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Asunto(s)

Bencimidazoles/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Química Farmacéutica , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

Asunto(s)

Bencimidazoles/química , Ácidos Carboxílicos/química , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Animales , Bencimidazoles/metabolismo , Ácidos Carboxílicos/metabolismo , Cromatografía Líquida de Alta Presión , Ciclohexanonas/química , Diacilglicerol O-Acetiltransferasa/metabolismo , Inhibidores Enzimáticos/análisis , Inhibidores Enzimáticos/metabolismo , Hepatocitos/química , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Isomerismo , Espectrometría de Masas , Ratones , Ratas

RESUMEN

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.

RESUMEN

The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).

RESUMEN

Studies have demonstrated that blockade of diacylglycerol acyltransferase 1 (DGAT1) leads to prolonged release of glucagon-like peptide 1 (GLP-1) after meal challenge. The current study was undertaken to investigate the mechanism of action underlying the elevated levels of GLP-1 release following pharmacological inhibition of DGAT1. We utilized a potent, specific DGAT1 inhibitor, compound A, to investigate the changes in intestinal lipid profile in a mouse model after oral administration of the compound and challenge with tracer containing fatty meal. [13C18]-oleic acid and LC-MS were employed to trace the fate of dietary fatty acids provided as part of a meal challenge in lean mice. Lipid profiles in plasma, proximal to distal segments of intestine, and feces were evaluated at various times following the meal challenge to study the kinetics of fatty acid absorption, synthesis into complex lipids, and excretion. Pharmacological inhibition of DGAT1 led to reduction of postprandial total and newly synthesized triglyceride (TG) excursion and significant increases in TG and FFA levels in the distal portion of intestine enriched with enteroendocrine L cells. Enhanced levels of FFA and cholesteryl ester were observed via fecal fat profiling. DGAT1 inhibition leads to enhancement of carbon flow to the synthesis of phosphatidylcholine within the intestine. DGAT1 inhibition markedly increases levels of TG and FFA in the distal intestine, which could be the predominant contributor to the prolonged and enhanced postprandial GLP-1 release. Inactivation of DGAT1 could provide potential benefit in the treatment of dysmetabolic diseases.

RESUMEN

We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 µM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.

RESUMEN

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

RESUMEN

Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

Asunto(s)

Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Glándulas Sebáceas/efectos de los fármacos , Glándulas Sebáceas/patología , Animales , Atrofia/inducido químicamente , Atrofia/enzimología , Biomarcadores/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Piel/efectos de los fármacos , Piel/enzimología , Piel/metabolismo , Bibliotecas de Moléculas Pequeñas/efectos adversos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología

RESUMEN

Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.

Asunto(s)

Isoindoles/síntesis química , Antagonistas del Receptor de Neuroquinina-1/síntesis química , Oxazoles/síntesis química , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Glucurónidos/metabolismo , Humanos , Isoindoles/química , Isoindoles/farmacocinética , Isoindoles/farmacología , Tasa de Depuración Metabólica , Antagonistas del Receptor de Neuroquinina-1/química , Antagonistas del Receptor de Neuroquinina-1/farmacocinética , Antagonistas del Receptor de Neuroquinina-1/farmacología , Oxazoles/química , Oxazoles/farmacocinética , Oxazoles/farmacología , Fragmentos de Péptidos/farmacología , Sustancia P/análogos & derivados , Sustancia P/farmacología

RESUMEN

OBJECTIVE: Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L. DESIGN AND METHODS: Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models. RESULTS: Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC). CONCLUSION: Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic.

Asunto(s)

Peso Corporal/efectos de los fármacos , Diacilglicerol O-Acetiltransferasa/metabolismo , Tracto Gastrointestinal/efectos de los fármacos , Animales , Composición Corporal , Cromatografía Liquida , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diacilglicerol O-Acetiltransferasa/genética , Modelos Animales de Enfermedad , Perros , Células Enteroendocrinas/efectos de los fármacos , Células Enteroendocrinas/metabolismo , Heces/química , Tracto Gastrointestinal/metabolismo , Ginsenósidos/farmacología , Células HT29 , Hormonas/metabolismo , Humanos , Inmunohistoquímica , Lactonas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Orlistat , Periodo Posprandial/efectos de los fármacos , Espectrometría de Masas en Tándem , Triglicéridos/sangre

RESUMEN

A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.

Asunto(s)

Benzazepinas/farmacología , Neuralgia/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Animales , Modelos Animales de Enfermedad , Ratas

RESUMEN

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

RESUMEN

We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.

RESUMEN

Parathyroid hormone (PTH) is the anabolic standard of care for patients with severe osteoporosis. The CaSR allosteric antagonist JTT-305/MK-5442, a PTH secretagogue, could offer an oral osteoanabolic treatment alternative for postmenopausal women with osteoporosis. Here we disclose the pharmacokinetic profile of JTT-305/MK-5442 and its activity on bone remodeling in ovariectomized (OVX) osteopenic rats. Daily treatments (0.3 to 2.4 mg/kg/d) for 12 weeks resulted in plateaued BMD increases (3.8 to 5.3%) at axial and appendicular skeletal sites. However, treatment effects were not statistically significant, in agreement with effects seen in animals treated with low dose PTH (1-84) (5 µg/kg/d). In a consecutive study we tested JTT-305/MK-5442 effects on bone formation in OVX-rats challenged with combined alendronate (ALN) treatment paradigms. At 7 month, JTT-305/MK-5442 treatment significantly increased BMD in lumbar vertebrae (LV), while no change in BMD was observed in femora or tibiae. ALN add-on co-treatment produced incremental increases in LV, distal femur (DF) and proximal tibia (PT) BMD over the respective ALN control. Histological analyses confirmed modest increases in mineralized surface (MS/BS) and bone formation rate (30.5±1.9%) on trabecular surfaces by JTT-305/MK-5442. As expected, ALN administration profoundly reduced bone formation, however, JTT-305/MK-5442 significantly stimulated MS/BS and BFR in ALN treated groups. In summary, JTT-305/MK-5442 acts as a PTH secretagogue in the osteopenic OVX-rat, eliciting consistent, though modest effects on remediation of BMD due to estrogen depletion. Induction of bone formation by JTT-305/MK-5442 at trabecular bone surfaces appears to be resilient to ALN-mediated suppression of bone formation. This study provides for the first time, a mechanistic evaluation of combination treatment of a PTH secretagogue with ALN.

Asunto(s)

Alendronato/administración & dosificación , Benzoatos/administración & dosificación , Conservadores de la Densidad Ósea/administración & dosificación , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Propanolaminas/administración & dosificación , Receptores Sensibles al Calcio/antagonistas & inhibidores , Animales , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/metabolismo , Enfermedades Óseas Metabólicas/patología , Remodelación Ósea/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Estrógenos/deficiencia , Femenino , Ovariectomía , Hormona Paratiroidea/sangre , Ratas , Ratas Sprague-Dawley

RESUMEN

Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.

Asunto(s)

Adamantano/uso terapéutico , Aminobenzoatos/uso terapéutico , Anilidas/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Ácido Graso Sintasas/antagonistas & inhibidores , Hígado Graso/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Animales , Antiinfecciosos/uso terapéutico , Modelos Animales de Enfermedad , Ácidos Grasos/biosíntesis , Glucosa/metabolismo , Humanos , Hígado/metabolismo , Ratones , Ratones Mutantes , Oxidación-Reducción , Esteroles/biosíntesis

RESUMEN

N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.

Asunto(s)

Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Indoles/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Perros , Haplorrinos , Humanos , Indoles/farmacocinética , Indoles/farmacología , Ratas

RESUMEN

Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 µCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (∼92%), with the majority of the dose (∼87%) excreted into faeces and a much smaller fraction (∼5%) into urine. Taranabant was absorbed rapidly, with C(max) of radioactivity attained at 1-2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised ∼12-24% and 33-42%, respectively, of the plasma radioactivity for up to 48 h. A second monohydroxylated metabolite, designated as M1a, represented ∼10-12% of the radioactivity in the 2- and 8-h postdose plasma profiles. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.

Asunto(s)

Amidas/farmacocinética , Piridinas/farmacocinética , Receptor Cannabinoide CB1/agonistas , Amidas/análisis , Amidas/metabolismo , Radioisótopos de Carbono/análisis , Agonismo Inverso de Drogas , Heces/química , Humanos , Masculino , Piridinas/análisis , Piridinas/metabolismo

RESUMEN

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing

Asunto(s)

Anticolesterolemiantes/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacocinética , Adolescente , Adulto , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/metabolismo , Biotransformación , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Heces/química , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Estructura Molecular , Oxazolidinonas/efectos adversos , Oxazolidinonas/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en Tándem , Adulto Joven

RESUMEN

High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.

Asunto(s)

Amidas/síntesis química , Amidas/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Receptores de Colecistoquinina/agonistas , Amidas/química , Animales , Fármacos Antiobesidad/química , Quimiocinas CC , Técnicas Químicas Combinatorias , Ingestión de Alimentos/efectos de los fármacos , Vaciamiento Vesicular/efectos de los fármacos , Humanos , Imidazoles/química , Ratones , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNa(v)1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10mg/kg.

Asunto(s)

Piridinas/química , Piridinas/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Analgésicos/química , Analgésicos/farmacología , Animales , Inflamación/tratamiento farmacológico , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7 , Dolor/tratamiento farmacológico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Relación Estructura-Actividad