RESUMO
Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Animais , Sítios de Ligação , Dipeptídeos/farmacologia , Cães , Metaloproteínas/antagonistas & inibidores , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
5,11-Dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7)90(4,9)]dodecane (2a) has been found to be a potent narcotic analgesic of unusual structure. All of the analgesic activity was attributable to the levorotatory isomer 2b which was approximately three times as potent as morphine in the rat. Removal of one N-methyl group from 2a reduced, but did not abolish, the analgesic activity. However N-allyl analogues were neither agonists nor antagonists. Replacement of one of the phenyls of 2a with a cyclohexyl group yielded an analogue with considerable activity. Structural similarities with derivatives of ethenooripavine are noted.
Assuntos
Analgésicos Opioides/síntese química , Compostos de Bifenilo/síntese química , Animais , Fenômenos Químicos , Química , Avaliação Pré-Clínica de Medicamentos , Isomerismo , Metilação , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
Eighteen species of Penicillium, one of Oidium and one of Paecilomyces were found to effect a stereospecific conversion of cis-propenylphosphonate to fosfomycin which was identified by paper chromatography and gas-liquid chromatography (GLC) of the trimethylsilyl esters. Penicillium spinulosum carried out the epoxidation only after the glucose substrate had been utilized. Glucose controlled the epoxidation since its residual concentrations in the broth severely depresses the reaction. At optimum levels of glucose, an epoxidation efficiency approaching 90% of olefin charged (0.2 g/liter) was obtained after 10 days of incubation. The olefin concentration could be increased to 0.5 g/liter when glucose was replaced by glycerol, whereby a 90% conversion to fosfomycin was attainable in 6 days. The high conversion efficiency, a good agreement between the GLC assay and bioactivity, are indicative of the levorotatory nature of the product.