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
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
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.