142580-65-2Relevant articles and documents
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
Cunico, Wilson,Ferreira, Maria de Lourdes G.,Wardell, James L.,Wardell, Solange M. S. V.
, p. 435 - 442 (2016)
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.]
Development of a new type of protease inhibitors, efficacious against FIV and HIV variants
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
, p. 1145 - 1155 (2007/10/03)
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.
Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
Parkes, Kevin E. B.,Bushnell, David J.,Crackett, Peter H.,Dunsdon, Stephen J.,Freeman, Andrew C.,et al.
, p. 3656 - 3664 (2007/10/02)
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.
