5452
J. J. Letourneau et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5449–5453
Table 3
H
N
b,c
a
O2N
Effect of compound 18c and Rimonabant on WIN 55,212-2 induced hypothermia in
mice
X
O2N
N
Br
Dose (lmol/kg, sc)
Percent ( sem) reversal of WIN 55,212-2
9
10a; X = CH
10b; X = N
(10
l
mol/kg, sc) induced hypothermia
18c
Rimonabant
H
N
d
0.01
0.1
0.3
1
—
—
—
—
—
—
À0.2 4.6
13.8 5.7
14.7 14.9
60.2 15.3
116.7 3.8
113.4 4.8
N
Ar
O
X
H2N
N
Ar
12a,b
3
e
11a; X = CH
11b; X = N
10
30
100
H
N
46.8 10.7
92.5 2.4
100.4 2.2
—
N
R
N
Ar
O
ED50 (95% Cl)
ꢀ30
0.8 (0.5–1.5)
13a-d
Scheme 2. Reagents and conditions: (a) 1-bromo-3-(bromomethyl)benzene or
2-bromo-6-(bromomethyl)pyridine, K2CO3, acetone, reflux; (b) Ar-B(OH)2, 1 N
Na2CO3 (aq), Pd(PPh3)4, dioxane, reflux; (c) raney Ni, H2 (1 atm), THF; (d) trimethy-
lacetylchloride, TEA, DCM; (e) 3-hydroxy-3-methylbutyric acid or 3-hydroxy-2,2-
dimethylpropanoic acid, DIPEA, HATU, DCM.
Table 4
Pharmacokinetic parameters for 18c in male Wistar rats at 5 mpk po and 1 mpk iva
AUCpo
1292 ng h/mL
0–7.5 h
Fpo (%)
CLiv (mL/min/kg)
37
19
Vss (L/kg)
1.2
1.0
c, d, e
O2N
a,b
T1/2, (h)
iv
X
O2N
Br
N
H
a
Vehicle for po dosing is 0.5% gelatin in 5% mannitol (aq) and for iv dosing is 20%
N,N-dimethylacetamide in saline.
N
H
14
15a; X = CH
15b; X = N
Compound 18c had reasonable oral bioavailability (F = 37%),
moderate clearance (CL = 19 mL/min/kg) and volume of distribu-
tion (Vss = 1.2 L/kg) and a half-life of 1 h.
H
N
f
Ar
O
N
X
In conclusion, we report a novel series of CB1 antagonists that
H2N
Ar
17a,b
were developed from
a benzimidazole-based screening hit.
N
Replacement of the benzimidazole scaffold with isosteric indole
and ‘inverted’ indole, and incorporation of a hydroxyl moiety into
the amide side-chain, led to structures with improved properties
including lower log P, enhanced aqueous solubility, and better sta-
bility to both human and mouse liver microsomes. In addition,
compound 18c demonstrated in vivo efficacy in a CB1 agonist in-
duced hypothermia model and was orally bioavailable in rat.
g
H
N
16a; X = CH
16b; X = N
N
R
Ar
O
N
18a-d
Scheme 3. Reagents and conditions: (a) 3-bromobenzyaldehyde or 2-bromo-5-
formylpyridine, NaOMe, MeOH; (b) TFA, Et3SiH, DCM; (c) NaH, THF; add CH3I; (d)
Ar-B(OH)2, 1 N Na2CO3 (aq), Pd(PPh3)4, dioxane, reflux; (e) raney Ni, H2 (1 atm),
THF; (f) trimethylacetylchloride, TEA, DCM; (g) 3-hydroxy-3-methylbutyric acid or
3-hydroxy-2,2-dimethylpropanoic acid, DIPEA, HATU, DCM.
Acknowledgements
We thank members of the ADME group at Pharmacopeia for met-
abolic stability testing and colleagues in the Chemistry, Molecular
Pharmacology and Pharmacology Departments at MSD Newhouse
for purity and structure determination, solubility measurements,
pharmacokinetic, bioanalytical and pharmacological testing.
were incorporated at the B-ring position as these substituents were
earlier demonstrated to be optimal for potency.
Four out of eight of the analogs in Table 2 met our requirement
for aqueous solubility (>10 lg/mL). Of these, compound 18c had
the best potency in the luciferase assay (5 nM), and it also had ade-
quate HLM stability (i.e., >50% remaining @ 0.5 h). In addition, this
compound is substantially less lipophilic than highly lipophilic CB1
antagonists such as Rimonabant (i.e., Rimonabant A log P = 7.02
versus compound 18c A log P = 3.60).3
References and notes
1. For recent reviews see: (a) Jagerovic, N.; Fernandez-Fernandez, C.; Goya, P. Curr.
Top. Med. Chem. 2008, 8, 205; (b) Lange, J. H. M.; Kruse, C. G. Drug Discovery
Today 2005, 10, 693. and references therein.
3. A log P values calculated using ADME Profiler: Program for discreet compound
analysis and calculation of physicochemical properties, version 1.6.0;
Pharmacopeia Inc., 2004.
Because it had the best balance of potency, microsomal stability
and aqueous solubility, compound 18c was further profiled in vivo
including an in vivo efficacy model (i.e., ability to reverse WIN
55,212-2 induced mouse hypothermia)12 and rat pharmacokinetics
(PK). Compound 18c demonstrated a partial reversal of hypother-
4. (a) Lange, J. H. M.; van Stuivenberg, H. H.; Veerman, W.; Wals, H. C.; Stork, B.;
Coolen, H. K. A. C.; McCreary, A. C.; Adolfs, T. J. P.; Kruse, C. G. Bioorg. Med. Chem.
Lett. 2005, 15, 4794; (b) Debenhaum, J. S.; Madsen-Duggan, C. B.; Walsh, T. F.;
Wang, J.; Tong, X.; Doss, G. A.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.;
Huang, C. R.-R. C.; Shen, C.-P.; Feng, Y.; Marsh, D. J.; Stribling, D. S.; Shearman, L.
P.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Goulet, M. T. Bioorg.
Med. Chem. Lett. 2006, 16, 681; (c) Ellsworth, B. A.; Wang, Y.; Zhu, Y.;
Annapurna, P.; Gerritz, S. W.; Sun, C.; Carlson, K. E.; Kang, L.; Baska, R. A.; Yang,
Y.; Huang, Q.; Burford, N. T.; Cullen, M. J.; Johnghar, S.; Behnia, K.;
Pelleymounter, M. A.; Washburn, W. N.; Ewing, W. R. Bioorg. Med. Chem. Lett.
2007, 17, 3978.
mia at a dose of 30
at a dose of 100 mol/kg (compound dosed sc) resulting in an ED50
of ꢀ30 mol/kg. In comparison, Rimonabant demonstrated an ED50
of 0.8
mol/kg in this model (Table 3).13 The relatively weak activ-
lmol/kg and nearly full reversal of hypothermia
l
l
l
ity of 18c in the mouse hypothermia model is perhaps due to lower
affinity of this compound at the mouse CB1 receptor versus the
human CB1 receptor.14 Rat PK data for compound 18c is summa-
rized in Table 4.
5. (a) Baldwin, J. J.; Burbaum, J. J.; Henderson, I.; Ohlmeyer, M. H. J. J. Am. Chem.
Soc. 1995, 117, 5588; (b) Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L. W.;