K. J. Hodgetts et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4359–4363
4363
10. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37.
of MAO activity in vivo and the potential for tyramine interaction
may be required to fully assess the risk of hypertension from using
compound 26 in a clinical setting.
11. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481.
12. Compounds were tested as previously described: Szallasi, A.; Blumberg, P. M.;
Annicelli, L. L.; Krause, J. E.; Cortright, D. N. Mol. Pharmacol. 1999, 56, 581.
13. Carrageenan-induced thermal hyperalgesia model of acute inflammatory pain
as described by: Field, M. J.; Oles, R. J.; Lewis, A. S.; McCleary, S.; Hughes, J.;
Singh, L. Br. J. Pharmacol. 1997, 121, 1513.
14. The brevity of the route to the 1,8-naphthyridine core allowed the introduction
of the [14C]-label at a late stage in the synthesis. The synthesis of the [14C]-
labeled ketone which was then used in the Friedlander cyclization (as outlined
in Scheme 1) is shown below.
Recent reports have indicated that administration of TRPV1
antagonists causes hyperthermia in rodents19 and humans.20 None
of the compounds in the current study were assessed in this para-
digm, however, we have previously reported that compound 2 in
rodents caused a significant increase in initial core body tempera-
ture an effect that was tolerated upon repeat dosing.6 It remains to
be established if this undesirable effect can be disconnected from
analgesic activity.
CF3
N
CF3
N
CF3
N
O
14
14
i
ii
Cl
CN
In summary, the 1,8-naphthyridine 2 demonstrated levels of
irreversible binding of radioactivity that exceeded our criteria for
a compound to advance into development. Substitution of either
the A- or D-ring of 2 by a more electron deficient surrogate was
investigated but no improvement in covalent binding was
observed. Replacement of the 1,8-naphthyridine by a pyrido[2,3-
b]pyrazine core led to the identification of compound 23 and a
significant lowering of the potential for reactive metabolite forma-
tion. Finally, the incorporation of a primary amide at the 5-position
of the A-ring, afforded 26 (hTRPV1 0.8 nM and rTRPV1 1.3 nM) and
minimal potential for covalent protein binding both in vitro and in
vivo. The amide 26 had excellent oral exposure across three species
and at high doses (100 mg/kg) in rat. The pyrido[2,3-b]pyrazine 26
displayed a good selectivity profile in an off-target screen of over
160 receptors, ion channels and enzymes although MAO inhibition
was identified as a potential issue that would need to be further
evaluated in preclinical studies. The overall profile of 26 made it
an excellent candidate for additional in vivo studies to assess the
pharmacological effects of a TRPV1 antagonist with moderate brain
penetration. In rats, 26 significantly attenuated inflammatory pain
in both an acute (carrageenan) and a sub-chronic (CFA) model, fur-
ther supporting the utility of a TRPV1 antagonist for the treatment
of inflammatory pain states (e.g., osteo-arthritis).
Reagents and conditions: (i) Zn(14CN)2, Pd2(dba)3, dppf, DMF, 100 °C (87%); (ii)
CH3MgBr, THF, À20 °C, H3O+ (78%).
15. The synthesis of the [14C]-labeled thiazole is outlined below.
O
O
O
N
N
N
i, ii
iii, iv
OH
CF3
v, vi
H2N
OEt
OEt
S
S
S
I
O
O
N
N
14
vii
NMe(OMe)
CF3
S
S
CF3
Reagents and conditions: (i) NIS, DMF, 60 °C (73%); (ii) tBuONO, THF, 50 °C (49%); (iii)
methyl 2,2,-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 85 °C (47%); (iv) 1 M NaOH,
dioxane, rt (93%); (v) (COCl)2, DMFcat, CH2Cl2 (99%); (vi) HN(OMe)MeÁHCl, NEt(iPr)2,
CH2Cl2 (61%); (vii) 14CH3MgBr, THF, À20 °C (84%).
16. Deady, L. W.; Korytsky, O. L.; Rowe, J. E. Aust. J. Chem. 1982, 35, 2025.
17. The dihydroxy-ketones used in the cyclization to pyrido[2,3-b]pyrazines were
prepared from the methyl ketone.
References and notes
1. Szallasi, A.; Cortright, D. N.; Blum, C. A.; Eid, S. R. Nat. Rev. Drug Disc. 2007, 6,
357.
2. Westaway, S. M. J. Med. Chem. 2007, 50, 2589; Gharat, L.; Szallasi, A. Drug Dev.
Res. 2007, 68, 477.
3. (a) DeSimone, R. W.; Hodgetts, K.; Krause, J. E.; White, G. PCT WO 02/08221.;
(b) Bakthavatchalam, R.; Hutchison, A.; DeSimone, R. W.; Hodgetts, K.; Krause,
J. E.; White, G. U.S. Patent 6,723,730, 2004.
CH2Br
O
CH(OH)2
O
ii, iii
i
Ar2
O
Ar2
Ar2
Reagents: (i) Br2, HBr, AcOH (67%); (ii) AgNO3, MeCN (93%); (iii) NaOAc, DMSO (95%).
18. Cui, M.; Honore, P.; Zhong, C.; Gauvin, D.; Mikusa, J.; Hernandez, G.; Chandran,
P.; Gomtsyan, A.; Brown, B.; Bayburt, E. K.; Marsh, K.; Bianchi, B.; McDonald, H.;
Niforatos, W.; Neelands, T. R.; Moreland, R. B.; Decker, M. W.; Lee, C.-H.;
Sullivan, J. P.; Faltynek, C. R. J. Neurosci. 2006, 26, 9385.
19. (a) Honore, P.; Chandran, P.; Hernandez, G.; Gauvin, D. M.; Mikusa, J. P.; Zhong,
C.; Joshi, S. K.; Ghilardi, J. R.; Sevcik, M. A.; Fryer, R. M.; Segreti, J. A.; Banfor, P.
N.; Marsh, K.; Neelands, T.; Bayburt, E.; Daanen, J. F.; Gomtsyan, A.; Lee, C. H.;
Kort, M. E.; Reilly, R. M.; Surowy, C. S.; Kym, P. R.; Mantyh, P. W.; Sullivan, J. P.;
Jarvis, M. F.; Faltynek, C. R. Pain 2009, 142, 27; (b) Tamayo, N.; Liao, H.; Stec, M.
M.; Wang, X.; Chakrabarti, P.; Retz, D.; Doherty, E. M.; Surapaneni, S.; Tamir, R.;
Bannon, A. W.; Gavva, N. R.; Norman, M. H. J. Med. Chem. 2008, 51, 2744; (c)
Garami, A.; Shimansky, Y. P.; Pakai, E.; Oliveira, D. L.; Gavva, N. R.; Romanovsky,
A. A. J. Neurosci. 2010, 34, 1435.
4. Zheng, X.; Hodgetts, K. J.; Brielmann, H.; Hutchison, A.; Burkamp, F.; Jones, A.
B.; Blurton, P.; Clarkson, R.; Chandrasekhar, J.; Bakthavatchalam, R.; De
Lombaert, S.; Crandall, M.; Cortright, D.; Blum, C. A. Bioorg. Med. Chem. Lett.
2006, 16, 5217.
5. Blum, C. A.; Zheng, X.; Brielmann, H.; Hodgetts, K. J.; Bakthavatchalam, R.;
Chandrasekhar, J.; Krause, J. K.; Cortright, D.; Matson, D.; Crandall, M.; Ngo, C.
K.; Fung, L.; Day, M.; Kershaw, M.; De Lombaert, S.; Chenard, B. L. Bioorg. Med.
Chem. Lett. 2008, 18, 4573.
6. Blum, C. A.; Caldwell, T.; Zheng, X.; Bakthavatchalam, R.; Capitosti, S.;
Brielmann, H.; De Lombaert, S.; Kershaw, M. T.; Matson, D.; Krause, J. E.;
Cortright, D.; Crandall, M.; Jones, A. B.; Martin, W. J.; Murphy, B. A.; Boyce, S.;
Mason, G.; Rycroft, W.; Perrett, H.; Conley, R.; Burnaby-Davies, N.; Chenard, B.
L.; Hodgetts, K. J. J. Med. Chem. 2010, 53, 3330.
7. Brent, R. L. Teratology 2001, 63, 106.
20. Gavva, N. R.; Treanor, J. J. S.; Garami, A.; Fang, L.; Surapaneni, S.; Akrami, A.;
Alvarez, F.; Bak, A.; Darling, M.; Gore, A.; Jang, G. R.; Kesslak, J. P.; Ni, L.;
Norman, M. H.; Palluconi, G.; Rose, M. J.; Salfi, M.; Tan, E.; Romanovsky, A. A.;
Banfield, C.; Davar, G. Pain 2008, 136, 202.
8. (a) Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Chem. Res. Toxicol.
2004, 17, 3; (b) Nassar, A. F.; Lopez, A. A. Curr. Opin. Drug Disc. Dev. 2004, 7, 126;
(c) Kalgutkar, A. S.; Soglia, J. R. Expert Opin. Drug Metab. Toxicol. 2005, 1, 91; (d)
Ju, C.; Uetrecht, J. P. Curr. Drug Metab. 2002, 3, 367.
9. Samuel, K.; Yin, W.; Stearns, R. A.; Tang, Y. S.; Chaudhary, A. G.; Jewell, J. P.;
Lanza, T., Jr.; Lin, L. S.; Hagmann, W. K.; Evans, D. C.; Kumar, S. J. Mass Spectrom.
2003, 38, 211.