RESUMO
The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB1 receptor inverse agonists (CB1RIAs) that have been reported to attenuate obesity and improve insulin sensitivity in the diet-induced obese (DIO) mouse model. However, chronic dosing of select compounds from the series showed time-dependent brain accumulation despite a low brain/plasma exposure ratio. To address this issue, a PEGylation approach was employed to identify a novel series of homodimeric 6-benzhydryl-4-amino-quinazoline-PEG conjugates with an extended half-life. The lead compound 18 engaged peripheral CB1Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study.
RESUMO
Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50â¯=â¯45â¯nM), and excellent potency at SGLT2 (IC50â¯=â¯1â¯nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (Fâ¯=â¯78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24â¯h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.
Assuntos
Derivados de Benzeno/farmacologia , Ciclobutanos/farmacologia , Glicosídeos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/química , Ciclobutanos/administração & dosagem , Ciclobutanos/química , Cães , Relação Dose-Resposta a Droga , Glicosídeos/administração & dosagem , Glicosídeos/química , Haplorrinos , Humanos , Camundongos , Estrutura Molecular , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Pirróis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.
RESUMO
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Células HEK293 , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos C57BL , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).
RESUMO
A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Esvaziamento da Vesícula Biliar/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Imidazóis/química , Imidazóis/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Humanos , Hipoglicemiantes/farmacologia , Imidazóis/farmacologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Phosphonium salt-activated, Pd-catalyzed Suzuki-Miyaura and Sonogashira cross-coupling reactions of cyclic 1,3-diones in the synthesis of ß-substituted cyclic enones are described. These transformations exhibit good isolated yield and high generality with respect to both substrates and coupling partners. Extension of the substrate scope to cyclic 1,3-dione equivalents, such as 2-cyanocyclohexanone (4), is also briefly examined.
RESUMO
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolonas/farmacologia , Inibidores da Topoisomerase/farmacologia , HumanosRESUMO
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-AtividadeRESUMO
A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Piperidinas/metabolismo , Ligação Proteica , Ratos , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/farmacologiaRESUMO
The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6nM with 34 being the most potent compound discovered (MMP-2 IC(50)=0.39nM and MMP-9 IC(50)=0.22nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.
Assuntos
Azepinas/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Azepinas/farmacocinética , Disponibilidade Biológica , Ciclização , Descoberta de Drogas , Concentração Inibidora 50 , Inibidores de Proteases/farmacocinética , EstereoisomerismoRESUMO
The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.
Assuntos
Alcinos/química , Compostos Heterocíclicos/química , Compostos Organofosforados/química , Catálise , Cobre/química , Paládio/químicaRESUMO
2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50=26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F=53%) and long human liver microsome stability (t(1/2)=62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.
Assuntos
Benzoxazinas/síntese química , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenho de Fármacos , Administração Oral , Animais , Benzoxazinas/química , Benzoxazinas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/genética , Cricetinae , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , RatosRESUMO
The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent JAK3 activity against isolated enzyme and in T-cells. One analog (32) showed unique biological effects during in vitro and in vivo tests including inhibition of STAT5 phosphorylation, blockade of mast cell responses, and reduction of JAK3 based effects in mice models of allergic disease.
Assuntos
Hipersensibilidade/tratamento farmacológico , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Estaurosporina/síntese química , Animais , Ciclização , Avaliação Pré-Clínica de Medicamentos , Mastócitos/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT5/metabolismo , Relação Estrutura-Atividade , Linfócitos T/enzimologiaRESUMO
2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
Assuntos
Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/análogos & derivados , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologiaRESUMO
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Administração Oral , Animais , Cricetinae , Gorduras na Dieta/administração & dosagem , Desenho de Fármacos , Humanos , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Camundongos , Quinolinas/síntese química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
Assuntos
Glicolatos/síntese química , Glicolatos/farmacologia , PPAR delta/agonistas , Técnicas de Química Combinatória , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Glicolatos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
The first direct arylation via C-OH bond activation of tautomerizable heterocycles has been achieved using phosphonium salts, on the basis of a combination of the phosphonium coupling and Suzuki-Miyaura cross-coupling conditions. Optimal reaction condition is obtained through screening of phosphonium salts, Pd catalysts, and bases. The direct arylation via C-OH bond activation tolerates a variety of tautomerizable heterocycles and aryl boronic acids. The mechanism of the Pd-catalyzed phosphonium coupling is proposed to proceed via a domino seven-step process including the unprecedented heterocycle-Pd(II)-phosphonium species. Application of the Pd-catalyzed direct arylation via C-OH bond activation using PyBroP leads to the most efficient synthesis of the biologically important 6-arylpurine ribonucleoside in a single step from unactivated and unprotected inosine.