98105-41-0Relevant articles and documents
New routes to ss-cycloalkylalanine derivatives using serine-derived organozinc reagents
Carrillo-Marquez, Tomas,Caggiano, Lorenzo,Jackson, Richard F. W.,Grabowska, Urszula,Rae, Alastair,Tozer, Matthew J.
, p. 4117 - 4123 (2007/10/03)
Two distinct routes to β-cycloalkylalanine derivatives have been developed. The first route employs the reaction of the iodoalanine-derived zinc-copper reagent 2 with cycloalk-l-en-3-yl phosphates, and the second uses the palladium-catalysed coupling of t
Renin Inhibitors. Syntheses of Subnanomolar, Competitive, Transition-State Analogue Inhibitors Containing a Novel Analogue of Statine
Boger, Joshua,Payne, Linda S.,Perlow, Debra S.,Lohr, Nancy S.,Poe, Martin,et al.
, p. 1779 - 1790 (2007/10/02)
Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin.Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3s,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histydyl-L-prolyl-L-phenylalanyl-L-histydyl-ACHPA-L-leucyl-L-phenylalanyl amide , with renin inhibitions of Ki=1.6 * 10-10 M (human kidney renin), IC50=1.7 * 10-10 M (human plasma renin), IC50=1.9 * 10-9 M (dog plasma renin), and IC50=2.1 * 10-8 M (rat plasma renin).This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1.Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies.Structure-activity results are presented that show the minimal N-terminus for these inhibitors.An ACHPA-containing pentapeptide, N--L-phenylalanyl-L-histydyl-ACHPA-L-lecyl-L-phenylalanyl amide , retained subnanomolar inhibitory potency.Molecular modelling studies are described that suggested the design of ACHPA.
