RESUMO
Several series of novel non-thiourea-containing aminopyrazine derivatives were designed based on the MK-2 inhibitors 1-(2-aminopyrazin-3-yl)methyl-2-thioureas. These compounds were synthesized and evaluated for their inhibitory activity against MK-2 enzyme in vitro. Compounds with low micromolar to sub-micromolar IC50 values were identified, and several compounds were also found to be active in suppressing the lipopolysaccharide (LPS)-stimulated TNFα production in THP-1 cells with minimum shift compared to their enzyme activity.
Assuntos
Desenho de Fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Pirazinas/síntese química , Pirazinas/farmacologia , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirazinas/químicaRESUMO
The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.
Assuntos
Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Propionatos/síntese química , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Ciclização , Modelos Animais de Doenças , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Propionatos/química , Propionatos/farmacocinéticaRESUMO
A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
Assuntos
Indolizinas/química , Indolizinas/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/metabolismo , Animais , Gerbillinae , Humanos , Indolizinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-ß-lactams can be effective CAIs.
Assuntos
Anticolesterolemiantes/síntese química , Imidazóis/síntese química , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Azetidinas , Ezetimiba , Imidazóis/química , Imidazóis/farmacologia , Absorção Intestinal/efeitos dos fármacos , Camundongos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24h in the gerbil foot-tapping model with an ID(50) of 0.02 mpk at both 0 and 24h, respectively.
Assuntos
Antidepressivos Tricíclicos/química , Antagonistas dos Receptores de Neurocinina-1 , Pirrolidinas/química , Animais , Antidepressivos Tricíclicos/síntese química , Antidepressivos Tricíclicos/farmacocinética , Cães , Humanos , Macaca mulatta , Microssomos/metabolismo , Ratos , Receptores da Neurocinina-1/metabolismo , Relação Estrutura-AtividadeRESUMO
Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
Assuntos
Descoberta de Drogas/métodos , Receptores Acoplados a Proteínas G/agonistas , Tiazolidinedionas/química , Animais , Camundongos , Camundongos Knockout , Ligação Proteica/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/agonistas , Tiazolidinedionas/farmacologiaRESUMO
Previous work on human NK(1) (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK(1) antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24h with ID(50)'s of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Pirróis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacocinética , Humanos , Pirróis/administração & dosagem , Pirróis/farmacocinéticaRESUMO
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Carboxiliases/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Propanóis/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carboxiliases/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Propanóis/síntese química , Propanóis/química , Propanóis/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
This Letter describes optimization of ghrelin receptor antagonists and inverse agonists starting from a screening hit.
Assuntos
Fármacos Antiobesidade/química , Receptores de Grelina/antagonistas & inibidores , Sulfonamidas/química , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Linhagem Celular , Desenho de Fármacos , Agonismo Inverso de Drogas , Humanos , Masculino , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , BenzenossulfonamidasRESUMO
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Administração Oral , Animais , Quimiotaxia , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Macaca mulatta , Modelos Químicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC(50) values as low as 15 nM, and suppress expression of TNFalpha in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure-activity relationship (SAR), and biological evaluation of these compounds are discussed.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tioureia/química , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Tioureia/farmacologia , Tioureia/uso terapêutico , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.
Assuntos
Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Concentração Inibidora 50 , Interleucina-2/antagonistas & inibidores , Interleucina-2/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/farmacologia , Imidazóis/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Animais , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dexfenfluramina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Técnicas In Vitro , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/agonistasRESUMO
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.
Assuntos
Ciclopentanos/química , Receptores CCR2/antagonistas & inibidores , Compostos de Espiro/química , Acetais/química , Acetais/farmacologia , Cristalografia por Raios X , Ciclopentanos/farmacologia , Humanos , Cinética , Conformação Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Receptores CCR2/metabolismo , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Piperidinas/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Pirróis/síntese química , Pirróis/farmacologia , Receptores da Neurocinina-1/metabolismo , Amidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos de Epóxi/química , Humanos , Hidroxilação , Metilação , Estrutura Molecular , Pirróis/química , Estereoisomerismo , Ureia/químicaRESUMO
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
Assuntos
Amidas/síntese química , Ciclopentanos/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Ciclopentanos/química , Ciclopentanos/farmacologia , Humanos , Técnicas In Vitro , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR2 , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Through modification of a screening hit we have discovered a structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), which has subsequently served as the departure point for an ongoing program targeting CCR2 antagonists. Optimization of 11 leading to antagonists 26 and 37 is described. Antagonist 26 was shown to have good oral bioavailability in rats. Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM).
Assuntos
Amidas/síntese química , Indenos/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Compostos de Espiro/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Antagonistas dos Receptores CCR5 , Quimiocina CCL2/farmacologia , Quimiotaxia de Leucócito , Técnicas In Vitro , Indenos/farmacocinética , Indenos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Receptores CCR2 , Receptores CCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores da Neurocinina-1/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.
Assuntos
Alendronato/análogos & derivados , Alendronato/síntese química , Conservadores da Densidade Óssea/síntese química , Pró-Fármacos/síntese química , Alendronato/farmacocinética , Animais , Densidade Óssea , Conservadores da Densidade Óssea/farmacocinética , Osteoporose/tratamento farmacológico , Pró-Fármacos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.