4032
A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
7. Abad-Zapatero, C.; Metz, J. T. Drug Discov. Today 2005, 10 7, 464.
References and notes
8. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 432.
9. Conway, E. A.; Giblin, G. M. P.; Gibson, M.; Hall, A.; Hayhow, T. G. C.; Healy, M.
P.; Hurst, D. N.; Kilford, I. R.; McKeown, S. C.; Naylor, A.; Price, H. S.; Rawlings,
D. A. WO2006/114313A1, 2006.
10. Attempts to oxidise the benzylic alcohol 4a resulted only in formation of
phthalimide 27(oxidation with PDC was also attempted but resulted in no
detectable aldehyde formation). Attempts to convert the hydroxyl group to a
leaving group and displace with amines resulted in formation of lactam 28
1. (a) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharmacol. Rev. 1994, 46, 205; (b)
Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, M. D. Annu. Rev.
Pharmacol. Toxicol. 2001, 41, 661; (c) Narumiya, S.; Sugimoto, Y.; Ushikubi, F.
Physiol. Rev. 1999, 79, 1193.
2. (a) Murakami, M.; Nakatani, Y.; Tanioka, T.; Kudo, I. Prostaglandins Other Lipid
Mediat. 2002, 68–69, 383; (b) Claveau, D.; Sirinyan, M.; Guay, J.; Gordon, R.;
Chan, C.-C.; Bureau, Y.; Riendeau, D.; Mancini, J. A. J. Immunol. 2003, 170, 4738;
(c) Trebino, C. E.; Stock, J. L.; Gibbons, C. P.; Naiman, B. M.; Wachtmann, T. S.;
Umland, J. P.; Pandher, K.; Lapointe, J.-M.; Saha, S.; Roach, M. L.; Carter, D.;
Thomas, N. A.; Durtschi, B. A.; McNeish, J. D.; Hambor, J. E.; Jakobsson, P.-J.;
Carty, T. J.; Perez, J. R.; Audoly, L. P. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 9044;
(d) Kamei, D.; Yamakawa, K.; Takegoshi, Y.; Mikami-Nakanishi, M.; Nakatani,
Y.; Oh-ishi, S.; Yasui, H.; Azuma, Y.; Hirasawa, N.; Ohuchi, K.; Kawaguchi, H.;
Ishikawa, Y.; Ishii, T.; Uematsu, S.; Akira, S.; Murakami, M.; Kudo, I. J. Biol. Chem
2004, 279, 33684.
O
O
Cl
Cl
N
Dess-Martin
periodinane
N
N
N
N
N
H
O
O
OH
CH2Cl2
O
4a
27
(i) MsCl, Et3N, CH2Cl2
3. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug Discov. Dev. 2007, 10, 597.
4. (a) Hall, A.; Atkinson, S. A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
Coleman, T.; Giblin, G. M. P.; Gleave, R. J.; Hammond, B.; Healy, M. P.; Johnson,
M. R.; Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Tang, S. P. Bioorg. Med.
Chem. Lett. 2006, 16, 3657; (b) Giblin, G. M. P.; Bit, R. A.; Brown, S. H.; Chaignot,
H. M.; Chowdhury, A.; Chessell, I. P.; Clayton, N. M.; Coleman, T.; Hall, A.;
Hammond, B.; Hurst, D. N.; Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Tang, S. P.; Wilson, A. W.; Wilson, R. Bioorg. Med. Chem. Lett. 2007, 17, 385; (c)
Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.; Clayton, N. M.; Coleman, T.;
Giblin, G. M. P.; Hammond, B.; Healy, M. P.; Johnson, M. R.; Metcalf, A.; Michel,
A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Sweeting, J. Bioorg. Med. Chem. Lett.
2007, 17, 732; (d) Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.; Clayton,
N. M.; Coleman, T.; Giblin, G. M. P.; Hammond, B.; Healy, M. P.; Johnson, M. R.;
Metcalf, A.; Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Sweeting, J.;
Winyard, L. Bioorg. Med. Chem. Lett. 2007, 17, 916; (e) Hall, A.; Atkinson, S.;
Brown, S. H.; Chessell, I. P.; Chowdhury, A.; Giblin, G. M. P.; Goldsmith, P.;
Healy, M. P.; Jandu, K. S.; Johnson, M. R.; Michel, A. D.; Naylor, A.; Sweeting, J.
Bioorg. Med. Chem. Lett. 2007, 17, 1200.
(ii) pyrrolidine, DMF, K2CO3
r.t. then 90oC.
O
N
Cl
N
N
O
28
.
11. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31, 591.
12. (a) Kostewicz, E. S.; Wunderlich, M.; Brauns, U.; Becker, R.; Bock, T.; Dressman,
J. B. J. Pharm. Pharmacol. 2005, 56, 43; (b) Galia, E.; Nicolaides, E.; Horter, D.;
Löbenberg, R.; Reppas, C.; Dressman, J. B. Pharm. Res. 1998, 15, 698.
13. Permeability for compounds in MDCK cells: 4h 521 nm/s, 4j 360 nm/s, 10b
318 nm/s.
14. Studies with mdr1a/b knockout mice (in the presence and absence of
5. McKeown, S. C.; Hall, A.; Giblin, G. M. P.; Lorthioir, O.; Blunt, R.; Lewell, X. Q.;
Wilson, R. J.; Brown, S. H.; Chowdhury, A.; Coleman, T.; Watson, S. P.; Chessell,
I. P.; Pipe, A.; Clayton, N. M.; Goldsmith, P. Bioorg. Med. Chem. Lett. 2006, 16,
4767.
6. Hall, A.; Bit, R. A.; Brown, S. H.; Chowdhury, A.; Giblin, G. M. P.; Hurst, D. N.;
Kilford, I. R.; Lewell, X.; Naylor, A.; Scoccitti, T. Bioorg. Med. Chem. Lett. 2008, 18,
1592.
GF120918,
a potent P-gp and BCRP inhibitor) indicated the poor oral
exposure of 4j was not due to P-gp or BCRP-mediated efflux.
15. Saunders, J. H.; Slocombe, R. J. Chem. Rev. 1948, 43, 205.
16. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed 2003, 42, 4302.
17. Dess, D. B.; Martin, J. C. J. Org. Chem 1983, 48, 4155.