DITEKIREN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C50H75N9O8
Molecular Weight	930.186
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC[C@H](C)[C@H](NC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CN=CN1)N(C)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)C(C)C)C(=O)NCC4=NC=CC=C4

InChI

InChIKey=SASWSEQJAITMKS-JJNNLWIXSA-N

InChI=1S/C50H75N9O8/c1-11-33(6)43(47(64)53-29-35-20-15-16-22-52-35)57-44(61)37(32(4)5)27-42(60)38(24-31(2)3)55-46(63)41(26-36-28-51-30-54-36)58(10)48(65)39(25-34-18-13-12-14-19-34)56-45(62)40-21-17-23-59(40)49(66)67-50(7,8)9/h12-16,18-20,22,28,30-33,37-43,60H,11,17,21,23-27,29H2,1-10H3,(H,51,54)(H,53,64)(H,55,63)(H,56,62)(H,57,61)/t33-,37-,38-,39-,40-,41-,42-,43-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://adisinsight.springer.com/drugs/800000424 | DOI: 10.1016/0378-5173(91)90415-K | (1997) Antihypertensive Drugs, page 84, retrieved from: https://books.google.ru/books?id=f8OO3B7eD6wC

Ditekiren is a relatively large renin inhibitor incorporating the hydroxyethylene isostere as well as both the P4 proline and P2’ isoleucine of angiotensinogen. Methylation of the P2-site histidine backbone nitrogen stabilizes the P2-P3 peptide bond towards degradation by chymotrypsin. Even though oral bioavailability was low, serum ditekiren levels were equivalent to 4–8 times the in vitro IC50 for renin inhibition for this peptide throughout the 2.5 h after oral administration that blood levels were monitored. In Na-depleted cynomolgus monkeys, oral dose elicited a hypotensive response that had not returned to baseline by 5 h. Ditekiren had been in phase II clinical trials for the treatment of heart failure and hypertension. However, these studies were discontinued.

Approval Year

PubMed

Title	Date	PubMed
Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.	2000-01	10617675
Additive combination studies of captopril and ditekiren, a renin inhibitor, in nonhuman primates.	1991	1893613
Disposition, metabolism, and excretion of U-71038, a novel renin inhibitor peptide, in the rat.	1989-09-01	2573495
[Clinical application of renin inhibitors in the treatment of hypertension].	1989-09	2687512
Systemic and renal haemodynamic effects of renin or angiotensin converting enzyme inhibition in non-human primates.	1989-04	2666613
Kinetics of the inhibition of human renin by an inhibitor containing a hydroxyethylene dipeptide isostere.	1987-12-01	3322403
An orally active inhibitor of renin.	1986-12	3539793
Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo.	1986-10	3531518

Sample Use Guides

In Vivo Use Guide

7.5 mg/kg/min

Route of Administration: Intravenous

Name

Type

Language

MCMC-6317

Preferred Name

English

DITEKIREN

Official Name

English

ditekiren [INN]

Common Name

English

tert-Butyl (2S)-2-[[(?S)-?-[[(1S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-5-methyl-4-[[(1S,2S)-2-methyl-1-[(2-pyridylmethyl)carbamoyl]butyl]carbamoyl]hexyl]carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylate

Systematic Name

English

DITEKIREN [USAN]

Common Name

English

L-HISTIDINAMIDE, 1-((1,1-DIMETHYLETHOXY)CARBONYL)-L-PROLYL-L-PHENYLALANYL-N-(2-HYDROXY-5-METHYL-1-(2-METHYLPROPYL)-4-(((2-METHYL-1-(((2-PYRIDINYLMETHYL)AMINO)CARBONYL)BUTYL)AMINO)CARBONYL)HEXYL)-N(SUP .ALPHA.)-METHYL-, (1S-(1R*,2R*,4R*(1R*,2R*)))-

Common Name

English

U-71038

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C270