(3S,4S)-4-Amino-3-hydroxy-5-cyclohexylpentanoic acid
Need Assistance?
  • US & Canada:
    +
  • UK: +

(3S,4S)-4-Amino-3-hydroxy-5-cyclohexylpentanoic acid

* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

Category
γ−Amino acids
Catalog number
BAT-006617
CAS number
105192-90-3
Molecular Formula
C11H21NO3
Molecular Weight
215.29
(3S,4S)-4-Amino-3-hydroxy-5-cyclohexylpentanoic acid
IUPAC Name
(3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid
Synonyms
ACHPA; Cyclohexylstatine
Purity
95%
Storage
Store at 2-8°C
InChI
InChI=1S/C11H21NO3/c12-9(10(13)7-11(14)15)6-8-4-2-1-3-5-8/h8-10,13H,1-7,12H2,(H,14,15)/t9-,10-/m0/s1
InChI Key
UQWNNUPJBDWRHC-UWVGGRQHSA-N
Canonical SMILES
C1CCC(CC1)CC(C(CC(=O)O)O)N
1. Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine
J Boger, L S Payne, D S Perlow, N S Lohr, M Poe, E H Blaine, E H Ulm, T W Schorn, B I LaMont, T Y Lin J Med Chem. 1985 Dec;28(12):1779-90. doi: 10.1021/jm00150a007.
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-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA-L -leucyl-L- phenylalanyl amide [Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3], with renin inhibitions of Ki = 1.6 X 10(-10) M (human kidney renin), IC50 = 1.7 X 10(-10)M (human plasma renin), IC50 = 1.9 X 10(-9)M (dog plasma renin), and IC50 = 2.1 X 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-[(ethyloxy)carbonyl]-L-phenylalanyl-L- histidyl-ACHPA-L-leucyl-L-phenylalanyl amide [Etoc-Phe-His-ACHPA-Leu-Phe-NH2,8], retained subnanomolar inhibitory potency. Molecular modelling studies are described that suggested the design of ACHPA.
2. Design of rat renin inhibitory peptides
K Y Hui, E J Holtzman, M A Quinones, N K Hollenberg, E Haber J Med Chem. 1988 Sep;31(9):1679-86. doi: 10.1021/jm00117a003.
Because several well-studied strains of rats manifest spontaneous hypertension, we set out to design a renin inhibitor suitable for use in this species. On the basis of the sequence of the renin substrate, a series of substrate analogue inhibitory peptides were synthesized by systematically modifying the P5, P3, P2, P1P1', P2', P3', and P4' positions. In assays against rat plasma renin, we found that modifications at the C-terminal segment have a marked influence on potency, and that a secondary butyl side chain at the P2' position is important for obtaining optimal activity. The structure at the P3' position, however, could vary considerably without significant effect. The steric effect of the P2 position was important; there an isopropyl side chain provided optimal binding between the inhibitor and the enzyme. At the P3 and P5 positions, potency appeared to depend on aromatic side chains. The effects at the P1P1' position of the transition-state residue (3S,4S)-4-amino-3-hydroxy -6-methylheptanoic acid (statine) and its congeners (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid (ACHPA) were found to depend on the sequence of the C-terminal segment. For peptides with an unfavorable C-terminal segment (-Ile-Phe-NH2), AHPPA and ACHPA resulted in a surprising retention of potency. For peptides with a favorable C-terminal segment (-Leu-Phe-NH2), the effect of AHPPA was mild, even though ACHPA still significantly enhanced potency. The hypotensive and plasma renin inhibitory effects of three of the analogues were then studied in anesthetized sodium-depleted rats. One of the compounds, acetyl-His-Pro-Phe-Val-Statine-Leu-Phe-NH2 (IC50 against rat plasma renin of 30 nM at pH 7.4), proved to be a potent hypotensive agent and a potentially useful probe for the study of the renin-angiotensin system in rats.
Online Inquiry
Verification code
Inquiry Basket