RESUMO
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
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.
Assuntos
Benzimidazóis/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Química Farmacêutica , Diacilglicerol O-Aciltransferase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzimidazóis/química , Ácidos Carboxílicos/química , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Animais , Benzimidazóis/metabolismo , Ácidos Carboxílicos/metabolismo , Cromatografia Líquida de Alta Pressão , Cicloexanonas/química , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/metabolismo , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Isomerismo , Espectrometria de Massas , Camundongos , RatosRESUMO
The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.
Assuntos
Acetamidas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/farmacocinética , Animais , Meia-Vida , Humanos , Pontos Quânticos , Ratos , Relação Estrutura-AtividadeRESUMO
MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Assuntos
Carbolinas/química , Carbolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Carbolinas/síntese química , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.
Assuntos
Metilaminas/química , Receptores de Somatostatina/química , Descoberta de Drogas , Humanos , Relação Estrutura-AtividadeRESUMO
The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.
Assuntos
Antibacterianos , Inibidores de beta-Lactamases , Humanos , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/química , Antibacterianos/química , Imipenem/farmacologia , beta-Lactamases , Bactérias Gram-Negativas , Testes de Sensibilidade MicrobianaRESUMO
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Pirazóis/química , Tiofenos/química , Oxirredutases do Álcool/metabolismo , Animais , Sítios de Ligação , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Rim/enzimologia , Rim/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêuticoRESUMO
Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.
Assuntos
Benzodiazepinas/química , Desenho de Fármacos , Receptores da Bombesina/agonistas , Sulfonamidas/química , Sulfonamidas/síntese química , Animais , Humanos , Camundongos , Ligação Proteica , Ratos , Receptores da Bombesina/metabolismo , Estereoisomerismo , Sulfonamidas/farmacocinética , TemperaturaRESUMO
The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed.
RESUMO
We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of â¼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Receptor de Insulina , Suínos , Porco Miniatura , Índice TerapêuticoRESUMO
Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, (2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg · kg(-1) · day(-1) reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain receptor occupancy was achieved at a plasma concentration of 0.34 ± 0.23 µM. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.
Assuntos
Fármacos Antiobesidade/farmacologia , Imidazóis/farmacologia , Pirazóis/farmacologia , Receptores da Bombesina/agonistas , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Receptores da Bombesina/análiseRESUMO
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor belonging to the subfamily of bombesin-like receptors. BRS-3 is implicated in the development of obesity and diabetes. We report here small-molecule agonists that are based on a 4-(alkylamino)pyridine-3-sulfonamide core. We describe the discovery of 2a, which has mid-nanomolar potency, selectivity for human BRS-3 versus the other bombesin-like receptors, and good bioavailability.
Assuntos
Piridinas/química , Receptores da Bombesina/agonistas , Sulfonamidas/farmacologia , Compostos de Sulfonilureia/farmacologia , Animais , Disponibilidade Biológica , Ligação de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacocinética , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinéticaRESUMO
GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Administração Oral , Animais , Concentração Inibidora 50 , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Assuntos
Piperazinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Haplorrinos , Camundongos , Obesidade/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (T(b)) is regulated in part by nutritional status, with a reduced T(b) during fasting. We report that fed Brs3 knockout mice have a lower T(b), which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) increase attenuated despite continued weight loss efficacy. The increase in T(b) was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a ß-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting T(b) reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, ß3-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted T(b) and the fasted, resting metabolic rates. The T(b) assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery.
Assuntos
Fármacos Antiobesidade/farmacologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores da Bombesina/agonistas , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Obesidade/fisiopatologia , Receptores da Bombesina/metabolismo , Redução de Peso/fisiologiaRESUMO
The original structure of a high-throughput screening hit obtained from an external vendor was revised based on multiple NMR studies. The active compound was re-synthesized via a novel route and its structure and biological activity as a BRS-3 agonist were unambiguously confirmed. Multi-gram quantities of the hit were prepared for pharmacokinetic and efficacy studies. The synthetic strategy allowed for the preparation of multiple analogs for SAR exploration.
Assuntos
Fármacos Antiobesidade/síntese química , Naftiridinas/síntese química , Pirazóis/síntese química , Receptores da Bombesina/agonistas , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacocinética , Ensaios de Triagem em Larga Escala , Humanos , Naftiridinas/química , Naftiridinas/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptores da Bombesina/metabolismo , Relação Estrutura-AtividadeRESUMO
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
Assuntos
Fármacos Antiobesidade/síntese química , Imidazóis/química , Receptores da Bombesina/agonistas , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Encéfalo/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/uso terapêutico , Camundongos , Obesidade/tratamento farmacológico , Ratos , Receptores da Bombesina/metabolismo , Relação Estrutura-AtividadeRESUMO
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Assuntos
Obesidade/tratamento farmacológico , Receptor Tipo 4 de Melanocortina/agonistas , Triazóis/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptor Tipo 4 de Melanocortina/genética , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.