RESUMO
As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Triazóis/farmacologia , Administração Oral , Animais , Cães , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Espiro/farmacologia , Animais , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Ratos Zucker , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain.
Assuntos
Hipoglicemiantes/farmacocinética , Fígado/enzimologia , Administração Intravenosa , Animais , Biotransformação , Canagliflozina/farmacocinética , Cromanos/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Glibureto/farmacocinética , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Metformina/farmacocinética , Ratos Sprague-Dawley , Ratos Zucker , Rosiglitazona , Especificidade da Espécie , Especificidade por Substrato , Sulfotransferases/metabolismo , Tiazolidinedionas/farmacocinética , TroglitazonaRESUMO
Fatty acid binding protein 3 (Fabp3) has been used as a serological biomarker of cardiac injury, but its utility as a preclinical biomarker of injury to skeletal muscle is not well described. Fabp3 concentrations were determined for tissues from Sprague-Dawley rats and found to occur at highest concentrations in cardiac muscle and in skeletal muscles containing an abundance of type I fibers, such as the soleus muscle. Soleus is also a primary site of skeletal muscle (SKM) injury caused by lipid-lowering peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists. In rats administered repeat doses of a PPAR-alpha agonist, the kinetics and amplitude of plasma concentrations of Fabp3 were consistent with plasma compound concentrations and histopathology findings of swollen, hyalinized, and fragmented muscle fibers with macrophage infiltration. Immunohistochemical detection of Fabp3 revealed focal depletion of Fabp3 protein from injured SKM fibers which is consistent with increased serum Fabp3 concentrations in treated rats. We then assessed the predictivity of serological Fabp3 for SKM necrosis in short duration toxicology studies. Rats were treated with various doses of 27 different compounds, and the predictivity of serological biomarkers was assessed relative to histology in individual rats and in treatment groups. Under these study conditions, Fabp3 was the most useful individual biomarker based on concordance, sensitivity, positive and negative predictive values, and false negative rate. In addition, the combination of Fabp3 and aspartate aminotransferase (AST) had greater diagnostic value than the conventional combination of creatine kinase-MM isoenzyme (CK) and AST.
Assuntos
Biomarcadores/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Músculo Esquelético , Miosite/metabolismo , Xenobióticos/toxicidade , Animais , Anticorpos Bloqueadores/farmacologia , Aspartato Aminotransferases/metabolismo , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/imunologia , Feminino , Masculino , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miocárdio/metabolismo , Miosite/induzido quimicamente , Miosite/patologia , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
Assuntos
Amidas/química , Desenho de Fármacos , Indóis/síntese química , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Técnicas de Química Combinatória , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Indóis/química , Indóis/farmacologia , Estrutura Molecular , RatosRESUMO
Novel tetrahydroisoquinolines have been developed as potent PPAR ligands. Evaluation of these compounds in PPARgamma responsive models of type 2 diabetes is described.
Assuntos
Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Camundongos , Modelos Moleculares , PPAR gama/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Rosiglitazona , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacocinética , Tiazolidinedionas/farmacologiaRESUMO
A new series of hPPARalpha agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARalpha agonist.
Assuntos
Propionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Triazóis/síntese química , Administração Oral , Animais , Apolipoproteína A-I/genética , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , Cães , Desenho de Fármacos , Humanos , Camundongos , Camundongos Transgênicos , Propionatos/química , Propionatos/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transfecção , Triazóis/química , Triazóis/farmacologiaRESUMO
PURPOSE: The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations. METHOD: For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. RESULT: The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.