4388
K. G. Rosauer et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4385–4388
Substitution of the triazolylmethyl group at N1 (43) led
to an improvement in cell-based GP inhibition (1.2 mM)
that revealed an apparent correlation between lactam
substituent polarity and improved cell activity.
McPherson, R. K.; Olson, T. V.; Treadway, J. L.; Hoover,
D. J. Chem. Biol. 2000, 7, 677. (b) Oikonomakos, N. G.;
Skamnaki, V. T.; Tsitsanou, K. E.; Gavalas, N. G.; Johnson,
L. N. Structure 2000, 8, 575.
9. Separation of racemic Boc-lactam 3 by chiral NP-HPLC
[chiral AD column; isocratic (92:8) heptane/iPrOH] afforded
individual enantiomers that were carried on as shown in
Scheme 1. A chiral synthesis of this peptidomimetic will be
reported separately.
Acknowledgements
A special thanks to Anthony Ogawa for his time during
many useful discussions and mentorship.
10. Phosphorolysis of glycogen using recombinant human
liver or muscle enzyme. Glucose-1-phosphate production was
monitored via an enzymatic assay involving phosphogluco-
mutase/glucose-6-phosphate dehydrogenase-mediated NADH
production (ex. 340 nm, em. 465 nm). The standard error for
liver and muscle enzyme activity is 0.17/0.14 (n>8), respec-
tively, based on an internal standard.
Phosphorylase a activity was measured at the sub-saturating
substrate levels in the physiologic glycogenolytic direction by a
modification (manuscript in preparation reference) of the
method in which glucose-1-phosphate production is coupled
to NAD reduction using phosphoglucomutase dehydrogenase.
For further details, see: Maddailh, V. T.; Madsen, N. B. J.
Biol. Chem. 1966, 241, 3873.
References and Notes
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Martin, W. H.; Hoover, D. J.; Armento, S. J.; Stock, I. A.;
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13. Not shown.
14. Glucagon-stimulated glycogenolysis in primary rat hepa-
tocytes. Inhibition of glucose production determined by
digesting remaining glycogen and quantifying by monitoring
glucose dehydrogenase-mediated NADPH production (ex. 340
nm, em. 465 nm). The standard error for hepatocyte activity is
0.15.
15. Due to incomplete solubility data, global logD calcula-
tions were performed on the compounds in Table 3 that
showed no sensitivity toward lactam N1-side-chain variation,
presumably due to the dominant effect of the 5-chloroindole
carboxamide moiety. Subsequent logD determination for
the truncated N1-substituted-3-acetamido-tetrahydroquinoline
yielded the noted correlative trend.
8. (a) Rath, V. L.; Ammirati, M.; Danley, D. E.; Ekstrom,
J. L.; Gibbs, E. M.; Hynes, T. R.; Mathiowetz, A. M.;