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
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.