916 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Letters
(8) (a) Corbett, A.; Tilton, R. G.; Chang, K.; Hasan, K. S.; Ido, Y.;
Wang, J . L.; Sweetland, M. A.; Lancaster, J . R.; Williamson, J .
R.; McDaniel, M. L.: Aminoguanidine, a novel inhibitor of nitric
oxide formation, prevents diabetic vascular dysfunction. Diabetes
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(10) (a) Garvey E. P.; Oplinger, J . A.; Tanoury, G. J .; Sherman, P.
A.; Fowler, M.; Marshall, S.; Harmon, M. F.; Paith, J . E.; Furfine,
E. S. Potent and selective inhibition of human nitric oxide
synthases: inhibition by non-amino acid isothioureas. J . Biol.
Chem. 1994, 269, 26669-26676. (b) Southan, G. J .; Szabo´, C.;
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(11) (a) Southan, G. J .; Szabo´, C.; O’Connor, M. P.; Salzman, A. L.;
Thiemermann, C. Amidines are potent inhibitors of nitric oxide
synthases: Preferential inhibition of the inducible isoform. Eur.
J . Pharmacol. 1995, 291, 311-318. (b) Moore, W. M.; Webber,
R. K.; Fok, K. F.; J erome, G. M.; Kornmeier, C. M.; Tjeong, F.
S.; Currie M. G. Inhibitors of human nitric oxide synthase with
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Med. Chem. 1996, 4, 1559-1564. (c) Garvey, E. P.; Oplinger, J .
A.; Furfine, E. S.; Kiff, R. J .; Laszlo, F.; Whittle, B. J . R.;
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timepoint was ∼10 µmol/kg). At the highest dose tested
(100 µmol/kg) (25) completely abolished all indications
of developing arthritis for the full 20 day duration of
the experiment. At the end of this period joints from
animals that had received the highest dose of 25 were
histologically indistinguishable from those of sham-
treated controls, suggesting that 25 may have disease-
modifying effects in addition to its antiinflammatory
actions in this model. It is noteworthy that this degree
of protection was not achieved by a maximally effective
dose of the standard antiinflammatory agent indometha-
cin. AR-C102222 was also effective when used in a more
therapeutic context: significant suppression of arthritis
was observed when dosing of 25 was started only when
symptoms of the developing arthritis were first detected
(10 days after adjuvant challenge).
Ack n ow led gm en t . We thank Phil Mallinder and
his colleagues in the Molecular Biology section at AZ
Charnwood for producing the recombinant human NOS
enzymes used in this study; also David Blake and Paul
Mapp (University of Bath, UK) for carrying out the
evaluation of compounds 23 and 25 in their rat adjuvant-
induced arthritis model.
Su p p or tin g In for m a tion Ava ila ble: Synthetic methods
and biological screen protocols. Microanalytical data and
representative spectra for compounds 11 and 16-26. Details
of parallel synthesis experiments. This material is available
(12) Beaton, H. G.; Hamley, P.; Nicholls, D. J .; Tinker, A. C.; Wallace,
A. V. 3,4-Dihydro-1-isoquinolinamines: A novel class of Nitric
Oxide Synthase Inhibitors with a range of isoform selectivity
and potency. Bioorg. Med. Chem. Lett. 2001, 11, 1023-1026.
(13) Beaton, H. G.; Boughton-Smith, N.; Hamley, P.; Ghelani, A.;
Nicholls, D. J .; Tinker, A. C.; Wallace, A. V. Thienopyridines:
Nitric oxide synthase inhibitors with potent in vivo activity.
Bioorg. Med. Chem. Lett. 2001, 11, 1027-1030.
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(18) Neither 9 nor any member of the aldehyde and ketone collection
used in this experiment gave a significant inhibition of isolated
i-NOS enzyme at the concentrations used in this study.
(19) This enantiomer was identified as having the R-configuration
from X-ray studies of enzyme inhibitor complexes (unpublished).
(20) Note that the ring systems are numbered differently, such that
C-5 in the quinazoline ring is spatially equivalent to C-8 of the
isoquinoline.
(21) Blake, D.; Mapp, P. Unpublished work.
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