RESUMEN
4-Substituted 2-amino-6-(anilino)pyrimidines have been found to be selective inhibitors of DNA polymerase III, a replicative enzyme known to be essential in the DNA synthesis of Gram-positive bacteria. Among the analogues, 18 displayed an IC(50) of 10 microM against DNA polymerase III from Staphylococcus aureus.
Asunto(s)
Compuestos de Anilina/síntesis química , Antibacterianos/síntesis química , ADN Polimerasa III/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Pirimidinas/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Antibacterianos/química , Antibacterianos/farmacología , ADN Polimerasa III/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , Pirimidinas/química , Pirimidinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Relación Estructura-ActividadRESUMEN
A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Enalapril/análogos & derivados , Enalapril/farmacología , Enalaprilato , Conformación Molecular , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
A series of potent inhibitors of angiotensin-converting enzyme (dipeptidyl carboxypeptidase, E.C. 3.4.15.1) derived from benzofused 1-carboxyalkyl-3-(1-carboxy-3-phenyl-propylamino) lactams (III) is described. In the most effective inhibitors (I50 2-4 X 10(-9)M) the lactam is 7 or 8 membered and the N-1 side chain is carboxymethyl or carboxyethyl. Conformational and steric factors pertinent to binding to the enzyme are discussed.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Lactamas/síntesis química , Indicadores y Reactivos , Lactamas/farmacología , Conformación Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Animales , Sitios de Unión , Dipéptidos/farmacología , Perros , Metaloproteínas/antagonistas & inhibidores , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
2-(Fluoromethyl)-3-(3,4-dihydroxyphenyl)alanine [alpha-FM-Dopa (I)] causes rapid, time-dependent, stereospecific, and irreversible inhibition of hog kidney aromatic amino acid (Dopa) decarboxylase. The inactivation occurs with loss of both the carboxyl carbon and fluoride from I and results in the stoichimetric formation of a covalent enzyme-inhibitor adduct. The data are consistent with I being a suicide inactivator of the enzyme, and a plausible mechanism for the inactivation process is presented. The inactivation is highly efficient in that there is essentially no enzymatic turnover of I to produce the corresponding amine, 1-(fluoromethyl)-2-(3,4-dihydroxyphenyl)ethylamine [alpha-FM-dopamine (II)]. Amine II is also a potent inactivator of the enzyme. In vivo compound I is found to inactivate both brain and peripheral (liver) Dopa decarboxylase activity. The possible significance of these data with respect to the known antihypertensive effect of I is discussed.