RESUMO
A novel series of HIV-1 integrase strand transfer inhibitors were designed using the venerable two-metal binding pharmacophore model and incorporating structural elements from two different literature scaffolds. This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral activity against HIV-1 and little loss of potency against the IN signature resistance mutations Q148K and G140S/Q148H.
Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV/síntese química , Lactamas/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Lactamas/farmacologia , MutaçãoRESUMO
[reaction: see text] 12-Oxatricyclo[6.3.1.0(2,7)]dodecanes can be efficiently synthesized in a stereoselective manner by Prins-pinacol reactions. By biasing the transition state of the Prins cyclization, it is possible to access either stereoisomer of this oxatricyclic ring system.
Assuntos
Alcanos/química , Cristalografia por Raios X , Ciclização , EstereoisomerismoRESUMO
Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 integrase inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of inhibitors.
Assuntos
HIV-1/enzimologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Animais , Masculino , Pirimidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-AtividadeRESUMO
Several highly deuterated analogs of the HIV-1 protease inhibitor brecanavir have been prepared to study the effect of deuterium upon metabolic stability. The sites for deuterium incorporation were initially chosen to maximize the potential for a kinetic isotope effect; locations where C-H bond breaking is the rate limiting step. The analogs have been profiled in both in vitro and in vivo pharmacokinetic studies and the result will be described herein.
Assuntos
Benzodioxóis/síntese química , Carbamatos/síntese química , Inibidores da Protease de HIV/síntese química , Administração Intravenosa , Animais , Área Sob a Curva , Benzodioxóis/química , Benzodioxóis/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Deutério/química , Deutério/farmacocinética , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Hepatócitos/metabolismo , Humanos , Taxa de Depuração Metabólica , Modelos Químicos , Estrutura Molecular , RatosRESUMO
Using a B-alkyl Suzuki cross-coupling as a key step, a concise and stereocontrolled synthesis of five- to eight-membered triisopropylsiloxy ethers having (2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(5,5-dimethoxypentylidene) side chains was developed. Prins-pinacol reactions of these precursors promoted by SnCl4 provide bicyclic products in which 5-, 6-, or 7-membered rings are joined by a C-C single bond. Synthetically challenging attached ring systems in which both rings are chiral can be prepared in this fashion with high stereo- and enantioselectivity. Stabilizing through-space electrostatic interactions between the alpha-alkoxycarbenium ion and an axially positioned oxygen substituent are believed to play a significant role in organizing the transition structure of the Prins cyclization.