RESUMO
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.
Assuntos
Analgésicos/síntese química , Naftiridinas/síntese química , Pirazinas/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Células COS , Capsaicina/farmacologia , Chlorocebus aethiops , Temperatura Alta , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Microssomos Hepáticos , Naftiridinas/química , Naftiridinas/farmacologia , Dor/tratamento farmacológico , Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/agonistasRESUMO
The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzimidazóis/química , Técnicas de Química Combinatória , Cães , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ansiedade/tratamento farmacológico , Sítios de Ligação , Técnicas de Química Combinatória , Depressão/tratamento farmacológico , Humanos , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
[reaction: see text] Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.
RESUMO
[reaction: see text] By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from ethyl 2-chlorooxazole-4-carboxylate (2) was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles.
Assuntos
Oxazóis/síntese química , Alquilantes , Fatores Biológicos/síntese química , Halogênios/química , Oxazóis/química , Paládio/químicaRESUMO
The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described. [reaction: see text]
