Chemistry Reference
In-Depth Information
improved potency and selectivity leading to 5, whereupon leverage of the
synthetic scope gave rise to advanced neutral 8 and basic 10 leads with
improved absorption. Both 8 and 10 projected to long human half-lives on the
basis of low clearance and moderate clearance/higher volume respectively
(Table 8.6). Finally, a potent and selective acidic clinical candidate 13 with low
clearance and an outstanding safety profile was identified. The excellent pre-
clinical profile derived from the property-based strategy detailed above has
successfully translated to once-daily oral pharmacokinetics in man.
References
1. V. Boswell-Smith, D. Spina and C. P. Page, Br. J. Pharmacol., 2006,
147(suppl. 1), S252.
2. S. P. H. Alexander, Br. J. Pharmacol., 2009, 158, S203.
3. N. K. Terrett, A. S. Bell, D. Brown and P. Ellis, Bioorg. Med. Chem. Lett.,
1996, 6, 1819.
4. N. Galie, H. A. Ghofrani, A. Torbicki, R. J. Barst, L. J. Rubin, D.
Badesch, T. Fleming, T. Parpia, G. Burgess, A. Branzi, F. Grimminger, M.
Kurzyna and G. Simonneau, New Engl. J. Med., 2005, 353, 2148.
5. H. Haning, U. Niewohner, T. Schenke, S. M. Es, G. Schmidt, T. Lampe
and E. Bischoff, Biorg. Med. Chem. Lett., 2002, 12, 865.
6. A. Daugan, P. Grondin, C. Ruault, A. -C. Le Monnier de Gouville, H.
Coste, J. Kirilovsky, F. Hyafil and R. Labaudiniere, J. Med. Chem., 2003,
46, 4525.
7. H. J. Shim, Y. C. Kim, J. H. Lee, B. O. Ahn, J. W. Kwon, W. B. Kim, I.
Lee and M. G. Lee, J. Pharm. Pharmacol., 2004, 56, 1543.
8. R. H. Cote, Int. J. Impot. Res., 2004, 16, S28.
9. A. Makhlouf, A. Kshirsagar and C. Niederberger, Int. J. Impot. Res., 2006,
18, 501.
10. H. A. Ghofrani, I. H. Osterloh and F. Grimminger, Nat. Rev. Drug Dis-
covery, 2006, 5,689.
11. D. G. Brown, C. R. Groom, A. L. Hopkins, T. M. Jenkins, S. H. Kamp,
M. M. O'Gara, H. J. Ringrose, C. M. Robinson and W. E. Taylor, Pat.
Appl., WO 2003/038080, 2003.
12. B. J. Sung, K. Y. Hwang, Y. H. Jeon, J. I. Lee, Y. S. Heo, J. H. Kim, J.
Moon, J. M. Yoon, Y. L. Hyun, E. Kim, S. J. Eum, S. Y. Park, J. O. Lee,
T. G. Lee, S. Ro and J. M. Cho, Nature, 2003, 425, 98.
13. C. M. N. Allerton, C. G. Barber, K. C. Beaumont, D. G. Brown, S. M.
Cole, D. Ellis, C. A. L. Lane, G. N. Maw, N. M. Mount, D. J. Rawson, C.
M. Robinson, S. D. A. Street and N. W. Summerhill, J. Med. Chem., 2006,
49, 3581.
14. M. E. Bunnage, J. P. Mathias, A. Wood, D. Miller and S. D. A. Street,
Bioorg. Med. Chem. Lett., 2008, 18, 6033.
15. N. Watanabe, H. Adachi, Y. Takase, H. Ozaki, M. Matsukura, K.
Miyazaki, K. Ishibashi, H. Ishihara, K. Kodama, M. Nishino, M. Kakiki
and Y. Kabasawa, J. Med. Chem., 2000, 43, 2523.
Search WWH ::
Custom Search