RESUMO
This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenho de Fármacos , Hipolipemiantes/síntese química , Quinolinas/química , Tetrazóis/síntese química , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/metabolismo , Cães , Feminino , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Injeções Intravenosas , Masculino , Camundongos , Camundongos Transgênicos , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Naftiridinas/farmacologia , Animais , HDL-Colesterol , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Naftiridinas/síntese química , Relação Estrutura-AtividadeRESUMO
Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC(50)) and CETP activity in human plasma (36 nM IC(50)) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED(50) of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development.
Assuntos
Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Ratos , Especificidade por SubstratoRESUMO
Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor superfamily that regulates multiple target genes involved in lipid metabolism. Cholesterol ester transfer protein (CETP) is a secreted glycoprotein that modifies high-density lipoprotein (HDL) particles. In humans, plasma CETP activity is inversely correlated with HDL cholesterol levels. We report here that PPARalpha agonists increase CETP mRNA, protein and accordingly its activity. In a human CETP transgenic animal model harboring the natural flanking regions (Jiang et al. in J Clin Investigat 90:1290-1295, 1992), both fenofibrate and a specific synthetic PPARalpha agonist LY970 elevated human CETP mRNA in liver, serum protein and CETP activity. In hamsters, the endogenous liver CETP mRNA level and the serum CETP activity were dose-dependently upregulated by fenofibrate. In addition Wy14643, a PPARalpha agonist, also significantly elevated CETP mRNA and activity. In a carcinoma cell line of hepatic origin, HepG2 cells, overexpression of PPARalpha resulted in increased CETP mRNA and agonist treatment further elevated CETP mRNA levels. We conclude that PPARalpha agonists upregulate CETP expression and activity and may play an important role in PPARalpha (agonist mediated HDL cholesterol homeostasis in humans.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Animais , Células Cultivadas , Proteínas de Transferência de Ésteres de Colesterol/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/genética , Cricetinae , Fenofibrato/farmacologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/genética , RNA Mensageiro/biossínteseRESUMO
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
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
Assuntos
Hipoglicemiantes/síntese química , PPAR delta/agonistas , PPAR gama/agonistas , Éteres Fenílicos/síntese química , Fenilpropionatos/síntese química , Aumento de Peso/efeitos dos fármacos , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , PPAR alfa/genética , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Estereoisomerismo , Ativação TranscricionalRESUMO
Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700 L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment.
Assuntos
Anticolesterolemiantes/farmacocinética , Benzodiazepinas/farmacocinética , Modelos Biológicos , Oxazolidinonas/farmacocinética , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Meia-Vida , Humanos , Fatores de TempoRESUMO
As master regulators of lipid metabolism the peroxisome proliferator activated receptor (PPAR) family controls a wide variety of cellular processes, and thus it is not surprising that a large effort has focussed on discovering agents to pharmacologically modulate activity of these receptors. Early generation PPAR ligands, such as the fibrates and the thiazolidinediones (TZDs), were discovered empirically through an in vivo structure activity relationship exercise, whereas currently PPAR ligands are more often identified through target based structural design using cloned and expressed receptors. Regardless of how they were discovered, the development and clinical use of PPAR ligands throughout the last decade has greatly advanced understanding of the physiological function and therapeutic value of modulating these receptors. This review will briefly examine the PPAR family and then outline in greater detail select PPAR ligands indicated for the treatment of metabolic disorders.
Assuntos
Doenças Metabólicas/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidores , Animais , Humanos , Ligantes , Doenças Metabólicas/metabolismo , Modelos Moleculares , Estrutura Molecular , Receptores Citoplasmáticos e Nucleares/fisiologia , Relação Estrutura-Atividade , Fatores de Transcrição/fisiologiaRESUMO
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
Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between these lipoprotein fractions. Therapy that modulates HDL metabolism to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estimated that for each mg/dL increase in plasma HDL cholesterol, there could be a 2-3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clinical trials, and two have been terminated for off-target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors.
Assuntos
Anticolesterolemiantes/síntese química , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/uso terapêutico , Benzodiazepinas/síntese química , Benzodiazepinas/uso terapêutico , HDL-Colesterol/sangue , Ensaios Clínicos Fase III como Assunto , Descoberta de Drogas , Humanos , Oxazolidinonas/síntese química , Oxazolidinonas/uso terapêutico , Fatores de Risco , Relação Estrutura-AtividadeRESUMO
The design and synthesis of dual PPAR gamma/delta agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}propionic acid is described. This compound dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats and produced less weight gain relative to rosiglitazone at an equivalent level of glucose control.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Indicadores e Reagentes , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD. In this study, we have identified a potent (IC50 approximately 24 nM) and selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674). In human apolipoprotein A-1 (apoA-1) transgenic mice, LY518674 produced a dose-dependent increase in serum HDL-c, resulting in 208 +/- 15% elevation at optimum dose. A new synthesis of apoA-1 contributed to the increase in HDL-c. LY518674 increased apoA-1 mRNA levels in liver. Moreover, liver slices from animals treated with LY518674 secreted 3- to 6-fold more apoA-1 than control liver slices. In cultured hepatocytes, LY518674 produced 50% higher apoA-1 secretion, which was associated with increase in radiolabeled methionine incorporation in apoA-1. Thus, LY518674 is a potent and selective PPARalpha agonist that produced a much greater increase in serum HDL-c than the known fibrate drugs. The increase in HDL-c was associated with de novo synthesis of apoA-1.