Hiv-1 protease inhibitors, and methods of making and using them

Details Hiv-1 protease inhibitors, and methods of making and using them Hiv-1 protease inhibitors, and methods of making and using them

C - Chemistry, Metallurgy

07

D

C07D 263/24 (2006.01) A61K 31/421 (2006.01) A61P 31/18 (2006.01)

Patent

CA 2667449

One aspect of the invention relates to the design, synthesis and biological activity of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidine-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. For example, the present invention relates to inhibitors with variations at the P2 phenyloxazolidine and the P2' phenylsulfonamide moieties. Remarkably, compounds with an (S)-enantiomer of substituted phenyloxazolidines at P2 show highly potent inhibitory activities against wild-type HIV-1 protease. In certain embodiments, the inhibitors of the invention have Ki values in low picomolar (pM) range. In certain embodiments, the inhibitors of the invention were shown to be active against a variety of multi-drug resistant (MDR) HIV-1 proteases, each representing different paradigm of drug resistance.

L'invention concerne, dans un aspect, la conception, la synthèse et l'activité biologique de nouveaux inhibiteurs de la protéase du VIH-1 incorporant N-phényloxazolidine-5-carboxamides dans le squelette (hydroxyéthylamino)sulfonamide comme ligands P2. Par exemple, l'invention concerne des inhibiteurs présentant des variations au niveau des fractions de P2 phényloxazolidine et de P2' phénylsulfonamide. A relever que des composés avec un (S)-énantiomère de phényloxazolines substituées à P2 présentent des activités inhibitrices particulièrement puissantes contre la protéase de VIH-1 de type sauvage. Dans certains modes de réalisation, les inhibiteurs ont des valeurs Ki dans une gamme picomolaire basse (pM). D'autres modes de réalisation montrent des inhibiteurs actifs contre une variété de protéases du VIH-1 résistantes à plusieurs médicaments (MDR), chacun représentant un paradigme différent de résistance aux médicaments.

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