RESUMO
The synthesis and structure-activity profile of a new class of potent and highly specific thromboxane A2 synthetase inhibitors is described. The most potent member of this series in vitro is determined to be imidazo[1,5-a]-pyridine-5-hexanoic acid (9).
Assuntos
Sistema Enzimático do Citocromo P-450 , Imidazóis/síntese química , Oxirredutases Intramoleculares , Oxirredutases/antagonistas & inibidores , Piridinas/síntese química , Tromboxano A2/biossíntese , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxanos/biossíntese , Animais , Plaquetas/enzimologia , Bovinos , Epoprostenol/biossíntese , Epoprostenol/metabolismo , Humanos , Imidazóis/farmacologia , Masculino , Prostaglandina-Endoperóxido Sintases/metabolismo , Piridinas/farmacologia , Ovinos , Relação Estrutura-AtividadeRESUMO
The synthesis of various substituted 5-amino-2-pyridinecarboxylic acids and their derivatives is described by three general methods: (1) reductive alkylation of methyl 5-amino-2-pyridinecarboxylates (2) and subsequent hydrolysis; (2) alkylation of the urethane (9), followed by hydrolysis; and (3) selective NaBH4 reduction of the appropriate amide of (2), followed by hydrolysis. A more specific process was used for the 5-(phenylamino) compound, i.e., nucleophilic displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate by sodioformanilide and subsequent hydrolysis. Many of these 2-pyridinecarboxylic acid derivatives were potent antihypertensive agents in the spontaneously hypertensive rat (SHR). Optimization of structural parameters for this activity yielded compounds 54, 55, 34, 65, and 22, which were selected for further study in the renal hypertensive dog (RHD). Based on these studies, one compound, 5-[(4-fluorobenzyl)amino]-2-pyridinecarboxylic acid (65), was selected for preclinical toxicity evaluation. Based on the toxicological findings, it was decided not to pursue compound 65 clinically.
Assuntos
Aminopiridinas/síntese química , Anti-Hipertensivos/síntese química , Ácidos Picolínicos/síntese química , Aminopiridinas/farmacologia , Animais , Fenômenos Químicos , Química , Cães , Hipertensão/tratamento farmacológico , Hipertensão Renal/tratamento farmacológico , Masculino , Ácidos Picolínicos/farmacologia , RatosRESUMO
Synthesis of various substituted 5-thio-2-pyridinecarboxylic acids and their derivatives is described by three methods, i.e., displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate (10) by a thiol anion, alkylation of methyl 5-thio-2-pyridinecarboxylate derived from reaction of the diazotized methyl-5-amino-2-pyridinecarboxylate (5) with thiocyanate followed by borohydride reduction of the product, and alkylation of 5-thio-2-pyridinecarbonitrile followed by hydrolysis. 5-Thio-2-pyridinecarbonitrile was obtained from butyl 6-methyl-3-pyridyl sulfoxide (2) by nitrosation and dehydration of the oxime. Many of these 5-thio-2-pyridinecarboxylic acid derivatives were orally active antihypertensive agents in the spontaneously hypertensive rat. Optimization of the structural parameters for this activity yiedled 5-[m-trifluorobenzyl) thio]-2-pyridinecarboxylic acid (41) and its sulfoxide, 42. Further biological studies with these compounds are described.