RESUMO
The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.
Assuntos
Ácidos Carboxílicos/síntese química , Ciclopentanos/síntese química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Ácidos Carboxílicos/química , Ciclopentanos/química , Estrutura Molecular , Receptores de Lisoesfingolipídeo/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Reumatoide/tratamento farmacológico , Química Farmacêutica/métodos , Desenho de Fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Interleucina-1beta/metabolismo , Ligantes , MAP Quinase Quinase Quinases/química , Camundongos , Estrutura Molecular , Proteínas Proto-Oncogênicas/química , Piridinas/farmacologia , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Histamínicos/metabolismo , Animais , Biomarcadores , Antagonistas dos Receptores Histamínicos/química , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/prevenção & controle , Ligantes , Locomoção/efeitos dos fármacos , Camundongos , Estrutura Molecular , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).
Assuntos
Aminas/química , Anti-Inflamatórios/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Dor/tratamento farmacológico , Pirimidinas/síntese química , Receptores Histamínicos/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/classificação , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/classificação , Ligantes , Camundongos , Estrutura Molecular , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , RatosRESUMO
Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.