Heterocyclic analogues of L-citrulline as inhibitors of the isoforms of nitric oxide synthase (NOS) and identification of N-delta-(4,5-dihydrothiazol-2-yl)ornithine as a potent inhibitor

Citation
S. Ulhaq et al., Heterocyclic analogues of L-citrulline as inhibitors of the isoforms of nitric oxide synthase (NOS) and identification of N-delta-(4,5-dihydrothiazol-2-yl)ornithine as a potent inhibitor, BIO MED CH, 7(9), 1999, pp. 1787-1796
Citations number
30
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
09680896 → ACNP
Volume
7
Issue
9
Year of publication
1999
Pages
1787 - 1796
Database
ISI
SICI code
0968-0896(199909)7:9<1787:HAOLAI>2.0.ZU;2-T
Abstract
L-Thiocitrulline is a known potent inhibitor of several isoforms of nitric oxide synthase (NOS). To explore the structure-activity relationships (SARs ) for this molecule in more depth than has previously been reported, three analogues substituted at the sulphur of the isothioureas have been synthesi sed. In two of these, the S-substituent was 'tied back' sterically by cycli sation to the nitrogen remote from the amino-acid unit. N-delta-(4,5-Dihydr othiazol-2-yl)ornithine was identified as an inhibitor of rat inducible and constitutive isoforms of NOS and of a constitutive NOS derived from a huma n tumour xenograft. Analogous N-delta-(thiazol-2-yl)ornithines were less ac tive, whereas the corresponding N-delta-(oxazol-2-yl)ornithine and N-delta- (pyrimidin-2-yl)ornithine failed completely to inhibit NOS. A new efficient preparation of the critical synthetic intermediate, N-alpha-Boc-thiocitrul line t-butyl ester, has been developed. Further exploration of the SAR with 2-amino-5-(heterocyclylthio)pentanoic acids (synthesised from 2-(Boc-amino )-5-bromopentanoic acid t-butyl ester), with N-(4-aminobutyl)thiourea and w ith 2-(4-aminobutylamino)-4,5-dihydrothiazole enabled refinement of our pre vious model for binding of the substrate, L-arginine, and the inhibitors to NOS. (C) 1999 Elsevier Science Ltd. All rights reserved.