- Crystal Structures of Two (3S,4aS, 8aS)-N-(1,1-dimethyl)decahydro-2-[(2R,3S)-2-hydroxy-arylsulfonyl]amino]-4-phenylbutyl]-3-isoquinolinecarboxamide. Hemihydrates: Compounds with Moderate Activity as Aspartyl Protease Inhibitors
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Abstract: The crystal structures of two hemihydrates of (3S,4aS, 8aS)-N-(1,1-dimethyl)decahydro-2-[(2R,3S)-2-hydroxy-3-[[arylsulfonyl]amino]-4-phenylbutyl]-3-isoquinolinecarboxamides [aryl?=?4-nitrophenyl: [(1:X?=?4-O2N)2·H2O]; and aryl?=?4-bromophenyl: [(1:X?=?4-Br)2·H2O] are reported. The chiral anhydrous compounds, prepared from (2S,3S)-Boc-phenylalanine epoxide, have been reported to exhibit moderate antimalarial activity in vitro against Plasmodium falciparum. The molecular conformations and major intermolecular interactions of the two hydrates are similar, despite there being two independent, albeit similar, molecules in [(1:X?=?Br)2·H2O] compared to only one in [(1:X?=?4-O2N)2·H2O]. A common feature of both structures is that each water molecule is linked to four molecules of 1 via classical hydrogen bonds to form [[(1:X)4(H2O)] units, (X?=?4-O2N or 4-Br). As a consequence of the water molecules in [(1:X?=?4-O2N)2·H2O] being in special positions and the slight differences between molecules, A and B, in [(1:X?=?4-Br)2·H2O], the former has as a symmetrical struture. Emanating from each water molecule in both structures are four chains of alternating molecules of water and 1: these are linked into three dimensional arrays. Compound [(1:X?=?4-O2N)2H2O] crystallizes in the monoclinic space group C2 with a?=?21.1431(9), b?=?10.4886(6), c?=?15.4597(9) ?, b?=?111.145(3)°and Z?=?4. Compound [(1:X?=?4-O2N)2H2O] crystallizes in the monoclinic space group P21 with a?=?11.0860(9), b?=?28.559(2), c?=?11.5220(10) ?, b?=?117.585(3)° and Z?=?4. Graphical Abstract: A feature of both structures is that each water molecule is linked to four molecules of the sulfonamide via classical hydrogen bonds.[Figure not available: see fulltext.]
- Cunico, Wilson,Ferreira, Maria de Lourdes G.,Wardell, James L.,Wardell, Solange M. S. V.
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- 2',6'-Dimethylphenoxyacetyl: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors
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Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P3-P2 quinaldic-valine portion of 1 was replaced by 2',6'-dimethylphenoxyacetyl. With EC50's in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P3-P2 position of hydroxyethylamine-based HIV protease inhibitors.
- Beaulieu, Pierre L.,Anderson, Paul C.,Cameron, Dale R.,Croteau, Gilbert,Gorys, Vida,Grand-Ma?tre, Chantal,Lamarre, Daniel,Liard, Francine,Paris, William,Plamondon, Louis,Soucy, Fran?ois,Thibeault, Diane,Wernic, Dominik,Yoakim, Christiane,Pav, Susan,Tong, Liang
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p. 1094 - 1108
(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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- 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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- A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity
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A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized.The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group.Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction.N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells.Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.
- Tucker, Thomas J.,Lumma, William C.,Payne, Linda S.,Wai, Jenny M.,Solms, S. Jane de,et al.
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p. 2525 - 2533
(2007/10/02)
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