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
Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub-types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.
RESUMO
We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.
Assuntos
Benzoatos/química , Benzoatos/farmacologia , Descoberta de Drogas , Microssomos/efeitos dos fármacos , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Microssomos/enzimologia , Prostaglandina-E Sintases/química , RatosRESUMO
Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30µM, and failed to inhibit human mPGES-2 at 62.5µM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Animais , Cristalografia por Raios X , Cães , Humanos , Piperidinas/farmacocinética , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.
Assuntos
Benzoatos/farmacologia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Benzoatos/química , Ratos , Difração de Raios XRESUMO
Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.
Assuntos
Ácido Benzoico/química , Picolinas/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Ácido Benzoico/farmacocinética , Ácido Benzoico/uso terapêutico , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Dor/tratamento farmacológico , Ligação Proteica , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed.
Assuntos
Benzoatos/farmacologia , Descoberta de Drogas , Naftalenos/farmacologia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Benzoatos/síntese química , Benzoatos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-AtividadeRESUMO
EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.
Assuntos
Analgésicos/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Cães , Meia-Vida , Humanos , Lipopolissacarídeos/toxicidade , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
Assuntos
Cinamatos/síntese química , Cinamatos/farmacocinética , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Humanos , Hipoglicemiantes/uso terapêutico , Ligantes , PPAR alfa/fisiologia , PPAR gama/fisiologia , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/uso terapêuticoRESUMO
Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a basic carboxypeptidase that functions as a fibrinolysis inhibitor through the cleavage of C-terminal lysine on partially degraded fibrin. Modulation of TAFI activity provides a potential therapy for thrombosis complications by potentiating fibrinolysis. In our study, we identified three novel TAFI inhibitors containing a cysteine backbone. Three cysteine derivatives, guanidinyl-L-cysteine, glycyl-L-cysteine, and glycyl-glycyl-L-cysteine were tested in TAFI substrate assays and showed K(app)(i)=0.08, 0.14, and 0.99 microM, respectively. Subsequent fibrinolysis assays confirmed their TAFI inhibitory activities. Guanidinyl-L-cysteine showed inhibitory activity in a human plasma clot lysis assay (IC(50)=9.4 microM). Identification of these cysteine derivatives represents an opportunity to develop potent and specific TAFI inhibitors.
Assuntos
Carboxipeptidase B2/antagonistas & inibidores , Cisteína/análogos & derivados , Cisteína/farmacologia , Fibrinólise/efeitos dos fármacos , Humanos , Cinética , Ligantes , Modelos Moleculares , Oligopeptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)alpha/gamma dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARgamma partial agonist with relatively less but significant PPARalpha agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARgamma full agonist with no PPARalpha activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased phosphoenol pyruvate carboxykinase in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better antidiabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced very low-density lipoprotein cholesterol, whereas, rosiglitazone increased very low-density lipoprotein cholesterol. LSN862, fenofibrate, and rosiglitazone produced maximal increases in high-density lipoprotein cholesterol of 65, 54, and 30%, respectively. These findings show that PPARgamma full agonist activity is not necessary to achieve potent and efficacious insulin-sensitizing benefits and demonstrate the therapeutic advantages of a PPARalpha/gamma dual agonist.
Assuntos
Alcinos/farmacologia , Cinamatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Adiponectina , Alcinos/química , Animais , Ligação Competitiva , Peso Corporal , Colesterol/metabolismo , HDL-Colesterol/metabolismo , VLDL-Colesterol/metabolismo , Cinamatos/química , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Fenofibrato/farmacologia , Regulação Enzimológica da Expressão Gênica , Glucose/metabolismo , Homozigoto , Humanos , Hiperlipidemias/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Cinética , Metabolismo dos Lipídeos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Transgênicos , Modelos Químicos , Ligação Proteica , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Ratos , Rosiglitazona , Tiazolidinedionas/farmacologia , Transfecção , Triglicerídeos/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.