- Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors
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In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a Ki of 2.1 nM and an EC50 of 0.64 μM. Further optimization by decoration of the P1′ side chain furnished an even more potent HIV-1 protease inhibitor (Ki = 0.8 nM, EC50 = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).
- Wu, Xiongyu,?hrngren, Per,Joshi, Advait A.,Trejos, Alejandro,Persson, Magnus,Arvela, Riina K.,Wallberg, Hans,Vrang, Lotta,Rosenquist, ?sa,Samuelsson, Bertil B.,Unge, Johan,Larhed, Mats
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supporting information; experimental part
p. 2724 - 2736
(2012/06/04)
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- Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol- containing transition-state mimic
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A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1′ group of the co
- Wu, Xiongyu,?hrngren, Per,Ekegren, Jenny K.,Unge, Johan,Unge, Torsten,Wallberg, Hans,Samuelsson, Bertil,Hallberg, Anders,Larhed, Mats
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p. 1053 - 1057
(2008/09/20)
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- HIV protease inhibitors
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Compounds of the formula (I): Wherein R1, R2, X and N are as defined in the specification; E is N, CH; A1 and A" are terminal groups as defined in the specification. The compounds have utility as HIV-I protease inhibitors.
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Page/Page column 59-60
(2008/06/13)
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- Microwave-accelerated synthesis of P1′-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
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Two series of P1′-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1′ side chain. High cellular antiviral potencies were encountered when the P1′ benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 μM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
- Ekegren, Jenny K.,Ginman, Nina,Johansson, ?sa,Wallberg, Hans,Larhed, Mats,Samuelsson, Bertil,Unge, Torsten,Hallberg, Anders
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p. 1828 - 1832
(2007/10/03)
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- A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold
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Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1′-P3′ residues and alteration of the tertiary alcohol absolute stereochemistry a
- Ekegren, Jenny K.,Unge, Torsten,Safa, Mayada Zreik,Wallberg, Hans,Samuelsson, Bertil,Hallberg, Anders
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p. 8098 - 8102
(2007/10/03)
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