From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 208

targeting immune responses demonstrates the complexity of the immune system
and our relatively weak understanding of the complex interplay between 40 þ
known chemokines and 19 receptors.
However, this same complex interplay between receptors and immune
responses also offers significant future opportunities for safe and ecacious
CCR5 agents (such as maraviroc) as our understanding develops. There is
growing evidence that CCR5 antagonists could have applications in a wide
range of alternative indications, from inflammation 100 and multiple sclerosis, 101
through to obesity, 102 cancer 103 and pain. 104 Given the costs of clinical trials,
key to the future exploitation of agents such as maraviroc will be the devel-
opment of more predictive animal models of human disease states.
Acknowledgements
Marcel de Groot is thanked for molecular modelling graphics.
References
1. H. Masur, M. A. Michelis, J. B. Greene, I. Onorato, R. A. Stouwe, R. S.
Holzman, G. Wormser, L. Brettman, M. Lange, H. W. Murray and S.
Cunningham-Rundles, New Engl. J. Med., 1981, 305, 1431-1438.
2. E. P. Gelmann, M. Popovic, D. Blayney, H. Masur, G. Sidhu, R. E. Stahl
and R. C. Gallo, Science, 1983, 220, 862-865.
3. R. C. Gallo, P. S. Sarin, E. P. Gelmann, M. Robert-Guroff, E.
Richardson, V. S. Kalyanaraman, D. Mann, G. D. Sidhu, R. E. Stahl, S.
Zolla-Pazner, J. Leibowitch and M. Popovic, Science, 1983, 220, 865-867.
4. Y. Mehellou and E. De Clercq, J. Med. Chem., 2010, 53, 521-538.
5. S. J. Little, S. Holte, J.-P. Routy, E. S. Daar, M. Markowitz, A. C.
Collier, R. A. Koup, J. W. Mellors, E. Connick, B. Conway, M. Kilby, L.
Wang, J. M. Whitcomb, N. S. Hellmann and D. D. Richman, New Engl.
J. Med., 2002, 347, 385-394.
6. J. P. Moore and R. W. Doms, Proc. Natl. Acad. Sci. U.S.A., 2003, 100,
10598-10602.
7. R. A. Weiss, Nature, 2001, 410, 963-967.
8. J. P. Moore and M. Stevenson, Nat. Rev. Mol. Cell Biol., 2000, 1, 40-49.
9. U. Weiss, Nature, 2001, 410, 961.
10. J. C. Stephens, D. E. Reich, D. B. Goldstein, H. D. Shin, M. W. Smith,
M. Carrington, C. Winkler, G. A. Huttley, R. Allikmets, L. Schriml, B.
Gerrard, M. Malasky, M. D. Ramos, S. Morlot, M. Tzetis, C. Oddoux, F.
S. di Giovine, G. Nasioulas, D. Chandler, M. Aseev, M. Hanson, L.
Kalaydjieva, D. Glavac, P. Gasparini, E. Kanavakis, M. Claustres, M.
Kambouris, H. Ostrer, G. Duff, V. Baranov, H. Sibul, A. Metspalu, D.
Goldman, N. Martin, D. Duffy, J. Schmidtke, X. Estivill, S. J. O'Brien
and M. Dean, Am. J. Hum. Genet., 1998, 62, 1507-1515.