- 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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- Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond between P3 and P2 Sites
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Incorporation of β-alanine or γ-aminobutyric acid in position P2 of ACHPA or LeuΨVal-based tetrapeptides gave highly active renin inhibitors (compounds V,VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin.Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range.Oral activity was achieved by incorporation of polar functionalities at the N-terminus of β-alanine-containing tetrapeptides.One of these compounds (XXVIII) was chosen for further studies.This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.
- Raddatz, Peter,Jonczyk, Alfred,Minck, Klaus-Otto,Schmitges, Claus Jochen,Sombroek, Jan
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p. 3267 - 3280
(2007/10/02)
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