464
S. W. Wright et al. / Bioorg. Med. Chem. Lett. 15 (2005) 459–465
and Dennis J. Hoover, Ronald B. Gammill, and Ber-
a
O
O
H2N
nard Hulin for helpful discussions during the course of
this work. The authors also wish to thank Gregory D.
Berger and Ralph W. Stevenson for their support of this
work.
N
H
b, c
Cl
d, e
H2N
N
O
O
References and notes
O
1. Fact Sheet No. 138. World Health Organization, Geneva,
2002.
2. (a) McCormack, J. G.; Westergaard, N.; Kristiansen, M.;
Brand, C. L.; Lau, J. Curr. Pharm. Des. 2001, 7, 1457; (b)
Consoli, A. Diabetes Care 1992, 15, 430.
N
HN
H
N
O
OH
Scheme 1. Reagents and conditions: (a) cyclopentanone, NaB-
H(OAc)3, AcOH, ClCH2CH2Cl, 25°C; (b) ClCH2COCl, Et3N, THF,
0°C; (c) NH4OH, 2-PrOH, 25°C; (d) 5-chloroindole-2-carbonyl
chloride, Et3N, THF, H2O, 25°C; (e) HCl, MeOH, H2O, 25°C.
3. Magnusson, I.; Rothman, D. L.; Katz, L. D.; Shulman, R.
G.; Shulman, G. I. J. Clin. Invest. 1992, 90, 1323.
4. Hellerstein, M. K.; Neese, R. A.; Linfoot, P.; Christiansen,
M.; Turner, S.; Letsher, A. J. Clin. Invest. 1997, 100,
1305.
5. Treadway, J. L.; Mendys, P.; Hoover, D. J. Expert Opin.
Invest. Drugs 2001, 10, 439.
triacetoxborohydride.10 If necessary, potentially reactive
functional groups were protected with acid—labile pro-
tecting groups prior to the reductive amination step.
Typically alcohols were protected as the vinyl ethers,
while 1,2-diols and 1,3-diols were protected as the aceto-
nides. The resulting secondary amines were then con-
verted to the glycine derivative by either (a) reaction
of the secondary amine with chloroacetyl chloride fol-
lowed by aminolysis using excess NH4OH, (b) coupling
to Boc-Gly-OH using 1,10-carbonyldiimidazole followed
by removal of the Boc group with aqueous HCl, or (c)
coupling to CBZ-Gly-Cl followed by hydrogenolysis of
the CBZ group. In all cases, the resulting glycine deriv-
ative was then acylated with 5-chloroindole-2-carbonyl
chloride under Schotten–Baumann conditions to afford
the target compound. Protecting groups, if present, were
removed last by hydrolysis with aqueous HCl.
6. (a) Lu, Z.; Bohn, J.; Bergeron, R.; Deng, Q.; Ellsworth, K.
P.; Geissler, W. M.; Harris, G.; McCann, P. E.; McKe-
ever, B.; Myers, R. W.; Saperstein, R.; Willoughby, C. A.;
Yao, J.; Chapman, K. Bioorg. Med. Chem. Lett. 2003, 13,
4125; (b) Ogawa, A. K.; Willoughby, C. A.; Bergeron, R.;
Ellsworth, K. P.; Geissler, W. M.; Myers, R. W.; Yao, J.;
Harris, G.; Chapman, K. T. Bioorg. Med. Chem. Lett.
2003, 13, 3408.
7. (a) Nakamura, T.; Takagi, M.; Ueda, N. WO 2003037864
A1 (Chem. Abstr. 2003, 138, 368761); (b) Birch, A. M.;
Morley, A. D.; Stocker, A.; Whittamore, P. R. O. WO
2003074532 A1 (Chem. Abstr. 2003, 139, 261278); (c)
Birch, A. M.; Morley, A. D. WO 2003074513 A2 (Chem.
Abstr. 2003, 139, 261174); (d) Morley A. D. WO
2003074485 A2 (Chem. Abstr. 2003, 139, 245896); (e)
Whittamore, P. R. O.; Bennett, S. N. L.; Simpson, I.WO
2003074531 A1 (Chem. Abstr. 2003, 139, 246010); (f)
Stocker, A.; Whittamore, P. R. O. WO 2003074517 A1
(Chem. Abstr. 2003, 139, 245897).
In summary, we have identified a structurally distinct
series of potent chloroindole inhibitors of human liver
glycogen phosphorylase, which lack the pendant phenyl
rings and chiral centers present in the previous series.
The simpler chloroindole glycine scaffold, coupled with
the exocyclic amide, has allowed facile analog produc-
tion and modification of physical chemical properties.
We expect these newer compounds to exhibit lower
overall hydrophobicity and an altered pharmacoki-
netic/pharmacodynamic profile as compared to previous
chloroindole compounds because of the introduction of
polar, hydrophilic side chains. While the X-ray crystal-
lographic structure revealed many binding similarities
to the earlier chloroindole norstatine analogs, the in vivo
performance of the chloroindole glycines is enhanced
over the previously reported compounds. In particular,
the N-cyclopentyl ethanolamine amide 2e and the N-
(4-tetrahydropyranyl) ethanolamine amide 3q have dis-
tinguished themselves by their ability to lower plasma
glucose in the ob/ob mouse model at low doses.
8. Rath, V. L.; Ammirati, A.; Danley, D. E.; Ekstrom, J. L.;
Gibbs, E. M.; Hynes, T. R.; Mathiowetz, A. M.;
McPherson, R. K.; Olson, T. V.; Treadway, J. L.; Hoover,
D. J. Chem. Biol. 2000, 7, 677.
9. (a) Hoover, D. J.; Lefkowitz-Snow, S.; Burgess-Henry, J.
L.; Martin, W. H.; Armento, S. J.; Stock, I. A.; McPher-
son, R. K.; Genereux, P. E.; Gibbs, E. M.; Treadway, J. L.
J. Med. Chem. 1998, 41, 2934; (b) Martin, W. H.; Hoover,
D. J.; Armento, S. J.; Stock, I. A.; McPherson, R. K.;
Danley, D. E.; Stevenson, R. W.; Barrett, E. J.; Treadway,
J. L. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1776.
10. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849.
11. (a) Engers, H. D.; Shechosky, S.; Madsen, N. B. Can. J.
Biochem. 1970, 48, 746; (b) Enzyme activity was measured
at 22°C in 100lL of buffer containing 50mM Hepes
(pH7.2), 100mM KCl, 2.5mM EGTA, 2.5mM MgCl2,
0.5mM glucose-1-phosphate, and 1mg/mL glycogen.
Phosphate was measured at 620nm, 20min after the
addition of 150lL of 1M HCl containing 10mg/mL
ammonium molybdate and 0.38mg/mL malachite green.
Test compounds were added to the assay in 5lL of 14%
DMSO prior to the addition of the enzyme and IC50
estimates were obtained from dose response curves deter-
mined in triplicate. The reported IC50 values are the mean
of at least three such determinations (IC50 > 500 nM are
the mean of at least two determinations).
Acknowledgements
The authors wish to thank Philip H. Sarges and Katie L.
Dugas for assistance with some of the biological assays
Wright, Stephen W.
