- Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains
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Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only p
- Tamamura, Hirokazu,Koh, Yasuhiro,Ueda, Satoshi,Sasaki, Yoshikazu,Yamasaki, Tomonori,Aoki, Manabu,Maeda, Kenji,Watai, Yoriko,Arikuni, Hisashi,Otaka, Akira,Mitsuya, Hiroaki,Fujii, Nobutaka
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p. 1764 - 1768
(2007/10/03)
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- Development of a new type of protease inhibitors, efficacious against FIV and HIV variants
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Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.
- Lee, Taekyu,Le, Van-Duc,Lim, Dongyeol,Lin, Ying-Chuan,Morris, Garrett M.,Wong, Andrew L.,Olson, Arthur J.,Elder, John H.,Wong, Chi-Huey
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p. 1145 - 1155
(2007/10/03)
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- Synthesis of the HIV-proteinase inhibitor Saquinavir: A challenge for process research
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The task of process research, namely developing efficient, economically and technically as well as ecologically feasible syntheses in time, is demonstrated on the HIV-proteinase inhibitor Saquinavir (1), a complex molecule comprising six stereo-centres. Based on the first 26-step research synthesis furnishing a 10% overall yield, process research established a new, short 11-step synthesis affording a 50% overall yield.
- Goehring, Wolfgang,Gokhale, Surendra,Hilpert, Hans,Roessler, Felix,Schlageter, Markus,Vogt, Peter
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p. 532 - 537
(2007/10/03)
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- Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
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Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials.Six approaches for the large-scale synthesis of this compound have been studied.All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5.They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation.The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1.Kilogram quantities of Ro 31-8959 have been prepared using this route.
- Parkes, Kevin E. B.,Bushnell, David J.,Crackett, Peter H.,Dunsdon, Stephen J.,Freeman, Andrew C.,et al.
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p. 3656 - 3664
(2007/10/02)
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- The Development of Cyclic Sulfolanes as Novel and High-Affinity P2 Ligands for HIV-1 Protease Inhibitors
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Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50+/-14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.
- Ghosh, Arun K.,Lee, Hee Yoon,Thompson, Wayne J.,Culberson, Chris,Holloway, M. Katharine,et al.
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p. 1177 - 1188
(2007/10/02)
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- Potent HIV Protease Inhibitors: The Development of Tetrahydrofuranylglycines as Novel P2 Ligands and Pyrazine Amides as P3-Ligands
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A series of protease inhibitors bearing constrained unnaturel amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral ac
- Ghosh, Arun K.,Thompson, Wayne J.,Holloway, M. Katharine,McKee, Sean P.,Duong, Tien T.,et al.
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p. 2300 - 2310
(2007/10/02)
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