C. E. Mowbray et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5857–5860
5859
Table 2
tities by virtue of the efficient and concise synthetic route. The
compound also has good aqueous solubility and formulation char-
acteristics which enable further in vivo evaluation. Clinical trials
evaluating the potential of 5 (UK-453,061, lersivirine) to treat
HIV infection are proceeding and further progress will be reported
in due course.14
In conclusion we have vindicated our design strategy; combin-
ing excellent broad spectrum anti-HIV activity, an encouraging
pre-clinical safety profile, and a high quality pharmacokinetic
and pharmaceutical profile through focusing on attaining the nec-
essary excellent physical properties. The improvements made in
LLE which ultimately drove this success and allowed selection of
alcohol 5 can be seen in Figure 2. We have subsequently applied
our learning about the benefits of employing cyanohalo- and dicy-
anophenoxy substituents discovered in this work to provide fur-
ther novel NNRTI series and will publish additional results
shortly.15
IC50 fold-resistance of selected pyrazoles versus RT enzymesa bearing NNRTI
resistance mutations cf. wild type
Efavirenz
3
4
5
6
12
17
K103N
Y181C
F227L
V106A
Y188C
K101E
P236L
V108I
L100I
44
2.3
1.5
4.7
15
0.3
9.4
0.4
11
2.9
11
1.8
2.7
5.0
14
0.6
5.6
0.9
7.6
4.3
1.6
1.6
4.7
1.4
0.4
5.0
1.3
6.8
4.5
5.2
1.2
3.2
3.6
3.4
0.2
6.2
1.1
4.8
3.1
1.1
3.3
4.8
0.1
4.4
0.4
4.4
5.0
1.5
2.4
2.6
5.0
3.7
0.4
6.2
1.8
9.3
5.9
7.5
2.2
0.4
1.8
0.8
3.8
2.8
1.0
5.6
2.5
13
8.9
L234I
12
a
Details of in vitro assays have been reported separately.13
apeutic window compared to the alcohols 4–7 with respect to off
target pharmacology as assessed in wide ligand profiling (data
not shown) and ion channel selectivity indicated in a dofetilide
binding assay.11 The alcohol 7 was vulnerable to metabolism in
microsomes presumably due to its increased lipophilicity and
introduction of a vulnerable benzylic methyl group. Replacing
the methyl group in 7 with a chlorine atom to give compound 6
improves resistance to oxidative metabolism but the log D of the
resulting molecule is too high leading to unacceptably fast glucu-
ronidation as determined in human hepatocytes. Finally we chose
alcohol 5 over the equipotent but slightly more lipophilic congener
4 due to its improved metabolic stability. Thus alcohol 5 was cho-
sen for further development on the basis of its compelling overall
in vitro profile. Subsequent studies also showed improvements,
notably reduced clearance and increased half life, in the in vivo
pharmacokinetic profile in rats for alcohol 5 compared to the ear-
lier lead 3 (Table 3).12
Acknowledgements
This Letter describes the work of a number of people in addition
to the authors. We would especially like to thank Lesley Fishburn
and Alex Martin for RT testing, Julie Mori and Caroline Smith-Bur-
chnell for antiviral testing and Gill Allan for metabolism studies.
References and notes
2. Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the
International AIDS Society-USA Panel: Hammer, S. M.; Eron, J. J., Jr.; Reiss, P.;
Schooley, R. T.; Thompson, M. A.; Walmsley, S.; Cahn, P.; Fischl, M. A.; Gatell, J.
M.; Hirsch, M. S.; Jacobsen, D. M.; Montaner, J. S. G.; Richman, D. D.; Yeni, P. G.;
Volberding, P. A. J. Am. Med. Assoc. 2008, 300, 555. For further information see
3. First paper in this series ‘Pyrazole NNRTIs 1: Design and Initial Optimization of
a Novel Template’ (a) Burt, C.; Corbau, R.; Mowbray, C. E.; Perros, M.; Tran, I.;
Stupple, P. A.; Webster, R.; Wood, A. Bioorg. Med. Chem. Lett. 2009, 19, 5599; (b)
Corbau, R. G.; Mowbray, C. E.; Perros, M.; Stupple, P. A.; Wood, A. World Patent
Application WO 200204424.
Compound 5 demonstrated excellent activity against large pan-
els of wild type and drug-resistant HIV consistent with the encour-
aging profile demonstrated against the isolated RT enzymes shown
above.13 Compound 5 can be readily prepared in multi-gram quan-
4. (a) Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881; (b) The same
concept was independently proposed by researchers at Pfizer and termed lipE.
Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Monica Correia, A.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 15,
4406.
Table 3
Rat pharmacokinetic data for key compounds (2 mg/kg, iv)
Compound
3
5
Cl (mL/min/kg)
Vd (l/kg)
T1/2 (h)
>100
1.3
0.1
25.9
1.6
1.6
5. Second paper in this series ‘Pyrazole NNRTIs 2: Exploring the Dependency of
Potency on Lipophilicity’; Burt, C.; Corbau, R.; Mills, J.; Mowbray, C. E.; Perros,
M.; Tran, I.; Price, D. A.; Selby, M. D.; Stupple, P. A.; Webster, R.; Wood, A. in
preparation.
6. Third paper in this series ‘Pyrazole NNRTIs 3: Optimisation of Physicochemical
Properties’: (a) Corbau, R.; Hawes, M.; Jones, L. H.; Mills, J. E.; Mowbray, C. E.;
Perros, M.; Selby, M. D.; Stupple, P. A.; Webster, R.; Wood, A. Bioorg. Med. Chem.
Lett. 2009, 19, 5603; (b) Jones, L. H.; Mowbray, C. E.; Price, D. A.; Selby, M. D.;
Stupple, P. A. World Patent Application WO 2002085860.
7. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato, M.; Stuart, D. I.;
Stammers, D. K. J. Med. Chem. 1999, 42, 4500.
8. Ren, J.; Nichols, C.; Bird, L. E.; Fujiwara, T.; Sugimoto, H.; Stuart, D. I.; Stammers,
D. K. J. Biol. Chem. 2000, 275, 14316.
9. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
10. The microsomal free fraction data for representative compounds shown in
Table 1 demonstrates that metabolic stability is not being significantly biased
by binding in this assay.
11. Finlayson, K.; Turnbull, L.; January, C. T.; Sharke, J.; Kelly, J. S. Eur. J. Pharmacol.
2001, 430, 147.
12. (a) Allan, G.; Davis, J.; Dickins, M.; Gardner, I.; Jenkins, T.; Jones, H.; Webster, R.;
Westgate, H. Xenobiotica 2008, 38, 620–640; (b) Walker, D. K.; Davis, J.; Houle,
C.; Gardner, I. B.; Webster, R. Xenobiotica 2009, 39, 534.
13. (a) Corbau, R., et al. Poster Presentation, 47th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Chicago, September 17-20, 2007.; (b)
Corbau, R.; Mori, J.; Phillips, C.; Fishburn, L.; Martin, A.; Mowbray, C.; Panton,
W.; Smith-Burchnell, C.; Thornberry, A.; Ringrose, H.; Knöechel, T.; Irving, S.;
Westby, M.; Wood, A.; Perros, M. Antimicrob. Agents Chemother. 2009, in press.
14. (a) Fätkenheuer, G.; Staszewski, S.; Plettenburg, A.; Hackman, F.; Layton, G.;
McFadyen, L.; Davis, J.; Jenkins, T. M. Abstract of Papers, Fourth International
AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention,
Sydney, Australia, July 22–25, 2007; (b) For current status of clinical trials see:
Figure 2. Plot of Àlog (RT IC50) against clog P for pyrazole series. The 45° lines
indicate equal values of LLE.