RESUMO
A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.
Assuntos
Antagonistas de Dopamina/síntese química , Antagonistas dos Receptores de Dopamina D2 , Atividade Motora/efeitos dos fármacos , Pirazinas/síntese química , Pirimidinas/síntese química , Animais , Apomorfina/farmacologia , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Haloperidol/farmacologia , Indicadores e Reagentes , Estrutura Molecular , Pirazinas/química , Pirazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Receptores de Dopamina D4 , Relação Estrutura-AtividadeRESUMO
A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4'' hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. When compared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of N-methyl, C-4'' epimers 3a and 9; and C-4'' amine 11 identify these compounds as the most interesting erythromycin A-superior agents. Compound 3a has been advanced to clinical study.