Článek shrnuje základní poznatky o farmakokinetickém profilu, metabolizmu a lékových interakcích rilpivirinu, nejnovějšího perorálního nenukleosidového inhibitoru reverzní transkriptázy 2. generace, který je určen pro dosud neléčené pacienty s HIV-1 infekcí. Faktor, který dominantně určuje vysokou rezistenční bariéru RPV, je jeho konformační flexibilita a adaptabilita, což je unikátní vlastnost diarylpyrimidinových inhibitorů (DAPY inhibitory - NNRTI 2. generace). Jsou analyzovány multicentrické studie ECHO a THRIVE, které prokázaly non-inferioritu RPV k EFV, jeho příznivý bezpečnostní profil a signifikantně méně nežádoucích účinků. Závěrem jsou zmíněna aktuální terapeutická doporučení pro léčbu onemocnění HIV/AIDS a místo rilpivirinu v současných terapeutických režimech.

The article summarizes the basic facts about the pharmacokinetic profile, metabolism and drug interactions of rilpivirine (RPV). This is the latest orally administered second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for antiretroviral-naive patients with HIV-l infection. Conformational flexibility and adaptabihty are the factors that dominantly determine the high resistance barrier of RPV and are the unique features of diarylpyrimidine inhibitors (DAPY inhibitors - 2nd-generation NNRTIs). Multicentre Studies ECHO and THRIVE are also reviewed. Current guidelines for the treatment of HIV/AIDS are mentioned as well as the role of RPV in current therapeutic regimens.

• MeSH
• HIV infekce farmakoterapie   imunologie   metabolismus   MeSH
• inhibitory reverzní transkriptasy * farmakokinetika   farmakologie   metabolismus   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• nitrily * farmakokinetika   farmakologie   metabolismus   terapeutické užití   MeSH
• pyrimidiny * farmakokinetika   metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM).

• MeSH
• HIV reverzní transkriptasa antagonisté a inhibitory   chemie   metabolismus   MeSH
• HIV-1 účinky léků   enzymologie   MeSH
• inhibitory reverzní transkriptasy chemie   metabolismus   farmakologie   MeSH
• konformace proteinů MeSH
• pyrimidiny chemie   metabolismus   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulového dockingu MeSH
• Publikační typ
• časopisecké články MeSH

With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o, o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o, o-difluoro- p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.

• Publikační typ
• časopisecké články MeSH