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1.
J Med Chem ; 43(10): 2019-30, 2000 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-10821714

RESUMEN

A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.


Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Mutación , Quinazolinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Alquinos , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , Benzoxazinas , Proteínas Sanguíneas/metabolismo , Ciclopropanos , VIH-1/genética , Humanos , Estructura Molecular , Oxazinas/sangre , Oxazinas/farmacología , Unión Proteica , Quinazolinas/sangre , Quinazolinas/farmacología , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacos
2.
Org Lett ; 2(20): 3119-21, 2000 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-11009360

RESUMEN

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.


Asunto(s)
VIH-1/enzimología , Quinolonas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Estereoisomerismo
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