J. Ruiz-Caro et al. / Bioorg. Med. Chem. Lett. 16 (2006) 668–671
671
CN
Acknowledgment
NHSO2CH3
N
CN
Gratitude is expressed to the National Institutes of Health
(AI44616, GM35208, and GM49551) for support.
N
HN
NH
N
N
N
N
H
NH
O
References and notes
delavirdine
rilpivirine
1. Jorgensen, W.L.; Ruiz-Caro, J.; Tirado-Rives, J.; Basava-
pathruni,A.;Anderson,K.S.;Hamilton,A.D.Bioorg.Med.
Chem. Lett., in press, doi:10.1016/j.bmcl.2005.10.038.
2. Lin, T. S.; Luo, M. Z.; Liu, M. C.; Pai, S. B.; Dutschman,
G. E.; Cheng, Y. C. Biochem. Pharmacol. 1994, 47, 171.
3. Ray, A. S.; Yang, Z.; Chu, C. K.; Anderson, K. S.
Antimicrob. Agents Chemother. 2002, 46, 887.
4. Balzarini, J.; Brouwer, W. G.; Dao, D. C.; Osika, E. M.; De
Clercq, E. Antimicrob. Agents Chemother. 1996, 40, 1454.
5. Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.;
Daeyaert, F. F. D.; Vinkers, M.; Van Aken, K. J. A.;
Arnold, E.; Das, K.; Kilonda, A.; Hoornaert, G. J.;
Compernoolle, F.; Cegla, M.; Azzam, R. A.; Andries, K.;
The most potent compounds reported here, 23g and h,
compare favorably with all of these limits, so optimism
can be expressed for acceptable oral bioavailability.
In general, NNRTIs are relatively hydrophobic, so solu-
bility is expected to be more problematic than cell perme-
ability.1,14 This is reflected in Table 4, and the compounds
whose oral bioavailabilities are known to be low, delavir-
dine, UC781, and TMC125, have QPlogS values of ꢀ5.5
or less. Many factors can limit bioavailability, but poor
aqueous solubility is not a desirable starting point.14
Rilpivirine is also predicted and reported15 to have very
low aqueous solubility and high serum–protein binding,
though the oral bioavailability in rats and dogs is 31–
32%.15 It has been proposed that rilpivirine gains bio-
availability by formation of aggregates in a specific size
range, which are absorbed and transported through the
lymphatic system.15,16 Rational design for such a feature
is currently elusive, so the maxim remains that oral for-
mulation of compounds with logS below ca. ꢀ5.5 is likely
to be difficult.11
´
de Bethune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.;
Janssen, P. A. J. J. Med. Chem. 2004, 47, 2550.
6. Ho, W.; Kukla, M. J.; Breslin, H. J.; Ludovici, D. W.;
Grous, P. P.; Diamond, C. J.; Miranda, M.; Rodgers, J. D.;
Ho, C. Y.; De Clercq, E.; Pauwels, R.; Andries, K.; Janssen,
M. A. C.; Janssen, P. A. J. Med. Chem. 1995, 38, 794.
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8. Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002, 43, 4729.
´
9. Udier-Blagovic, M.; Tirado-Rives, J.; Jorgensen, W. L. J.
Am. Chem. Soc. 2003, 125, 6016.
10. Jorgensen, W. L. QikProp, v 2.3; Schro¨dinger LLC:
New York, 2005.
11. Jorgensen, W. L.; Duffy, E. M. Adv. Drug Deliv. Rev.
2002, 54, 355.
12. Morelock, M. M.; Choi, L. L.; Bell, G. L.; Wright, J. L. J.
Pharm. Sci. 1994, 83, 948.
13. Lipinski, C. A.; Lombardo, F.; Domini, B. W.; Feeney, P.
J. Adv. Drug. Deliv. Rev. 1997, 23, 3.
14. Jorgensen, W. L. Science 2004, 303, 1813.
15. Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.;
de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.;
Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.;
In conclusion, a joint computational and experimental
study has been carried out to develop new NNRTIs
which combine good efficacy, desirable pharmacologi-
cal properties, and ease of synthesis. This general goal
for drug discovery has been pursued here with the aid
of a computational approach featuring lead genera-
tion with the ligand-growing program BOMB, lead-
optimization with free-energy perturbation calcula-
tions, and prediction of pharmacological properties
with QikProp. In concert with synthetic forethought
in proposing lead templates, the present approach
facilitated identification of 10–30 lM lead compounds,
which could rapidly be refined to a 10 nM NNRTI
with predicted properties that are auspicious for oral
formulation.
´
Andries, K.; de Bethune, M.-P.; Pauwels, R.; Das, K.;
Clark, A. D., Jr.; Frenkel, Y. V.; Hughes, S. H.; Medaer,
B.; de Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.;
Williams, P.; Stoffels, P. J. Med. Chem. 2005, 48, 1901.
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Lewi, P. J.; Janssen, P. A. J.; Arnold, E. J. Med. Chem.
2005, 48, 1974.