R. J. Gleave et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6578–6581
6581
Table 4
final synthetic step. This involved introducing the amine substitu-
ent first, followed by boronic acid formation via lithiation and
Suzuki–Miyaura coupling with the desired 2-halopyridine.
The screening results (Table 4) revealed some interesting SAR.
The introduction of a second pyridine seemed to be well tolerated,
although substituents are required for activity (27). The 5-chloro
pyridine (25) shows improved potency over the 3-chloropyridine
(28), however a combination of these substituents shows no
improvement (26). Polar substituents are tolerated at the 3-posi-
tion, for example, 33. Whilst the 3,4-dichloro analogue was not
synthesised due to concerns over reactivity, the bicyclic analogue
34 shows encouraging potency and could be an interesting lead
for further chemistry.
SAR of heteroaryl substituents (compounds 33–38)
N
N
a
Aryl
CB2 pEC50
(efficacy)
cLog D at
pH 7.4
Rat Cli
(mL/min/g)
Cl
25
7.0 (101)
3.9
13
N
Cl
Cl
Analogue 25 had yielded a decrease in metabolic turnover when
compared to the lead. It was decided to combine the morpholine
substituent, found in compound 2, with the bi-pyridyl template,
however all analogues synthesized had no significant CB2 activity.
In conclusion, investigation of SAR around the lead 2-amino
pyridine (1) revealed a range of potent CB2 agonists with high
CB1 receptor selectivity. Several strategies were used to address
the observed metabolic liability. An investigation of the SAR with
the aim of lowering the overall lipophilicity was carried out. The
observed correlation of metabolic stability with calculated lipo-
philicity was poor, however this work identified some analogues
with improved in vitro stability. This however did not translate
to an acceptable value in vivo. Introduction of an electron-with-
drawing group to the central ring generally led to a loss of activity
and showed no benefit in terms of stability. Finally introduction of
a second heteroaryl was well tolerated by the receptor, and led to
some reduction in the in vitro metabolic turnover, however low
in vivo metabolism remained elusive.
26
27
28
6.5 (100%)
5.0 (29%)
6.3 (103%)
4.8
3.1
3.9
—
—
—
N
N
Cl
N
N
29d
6.4 (75%)
2.8
—
N
30d
31d
32d
6.1 (86%)
5.9 (102%)
6.0 (91%)
3.4
3.8
2.2
—
—
—
References and notes
N
N
1. Pertwee, R. G. Pharmacol. Ther. 1997, 74, 129.
2. Brown, A. J. Br. J. Pharmacol. 2007, 152, 567.
3. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. L. Nature
1990, 346, 561.
4. Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, W. A.; Devane, W. A.;
Felder, C. C.; Herekenham, M.; Mackie, K.; Martin, B. R.; Mechoulam, R.;
Pertwee, R. G. Pharmacol. Rev. 2002, 54, 161.
5. Buckley, N. E.; McCoy, K. L.; Mezey, E.; Bonner, T.; Zimmer, A.; Felder, C. C.;
Glass, M.; Zimmer, A. Eur. J. Pharmacol. 2000, 396, 141.
6. Stella, N. Glia 2004, 48, 267.
7. Van Sickle, M. D.; Duncan, M.; Kingsley, P. J.; Mouihate, A.; Urbani, P.; Mackie,
K.; Stella, N.; Makriyannis, A.; Piomelli, D.; Davison, J. S.; Marnett, L. J.; Di
Marzo, V.; Pittman, Q. J.; Patel, K. D.; Sharkey, K. A. Science 2005, 310, 329.
8. Foa, A.; Bevan, S. Expert Opin. Investig. Drugs 2005, 14, 695.
9. Burns, T. L.; Ineck, J. R. Ann. Pharmacoth. 2006, 40, 251.
10. Jhaveri, M. D.; Sagar, D. R.; Elmes, S. J. R.; Kendall, D. A.; Chapman, V. Mol.
Neurobiol. 2007, 36, 26.
11. Cheng, Y.; Hitchcock, S. A. Expert Opin. Investig. Drugs 2007, 16, 951.
12. Giblin, G. M. P.; O’Shaughnessy, C. T.; Naylor, A.; Mitchell, W. L.; Eatherton, A. J.;
Slingsby, B. P.; Rawlings, A.; Goldsmith, P.; Brown, A. J.; Haslam, C. P.; Clayton,
N. M.; Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R. J. Med. Chem.
2007, 50, 2597.
H2N
H2N
N
N
33
6.9 (86%)
7.2 (80%)
2.9
—
O
34
3.5
>50
13. Malan, T. P.; Ibrahim, M. M.; Deng, H.; Liu, Q.; Mata, H. P.; Vanderah, T.;
Porreca, F.; Makriyannis, A. Pain 2001, 93, 239.
N
14. Intravenous pharmacokinetics were assessed using the hydrochloride salt
dissolved in 0.9% (w/v) saline containing 2% (v/v) DMSO, 10% (w/v) Kleptose.
Following a 1 h intravenous infusion (target dose 1 mg/kg), 2 showed a blood
clearance of 89 mL/min/kg, with a steady-state volume of distribution (Vss) of
7.5 L/kg and a terminal half-life of 1.7 h.
a/d
See footnote to Table 1 for details. No significant CB1 activity was observed at
analogue concentrations up to 30 M.
l
15. Details of the yeast CB-2 reporter assay used to assess potency are given in:
Eartherton, A. J.; Giblin, G. M. P.; Mitchell, W. L.; Naylor, A.; Rawlings, D. A.
World patent WO 2005 074939.
acid via a Suzuki–Miyaura coupling then reaction with POCl3 to re-
place the methoxy with a chloro substituent. An alternative strat-
egy was also developed to enable the aryl to be introduced as the
16. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31, 591.