136630-89-2Relevant academic research and scientific papers
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.
Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond between P3 and P2 Sites
Raddatz, Peter,Jonczyk, Alfred,Minck, Klaus-Otto,Schmitges, Claus Jochen,Sombroek, Jan
, p. 3267 - 3280 (2007/10/02)
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.
