R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
1317
Steinberg, N. G.; Buchschacher, P.; Fried, J. H.; Kent, G.
J.; Tishler, M. J. Am. Chem. Soc. 1963, 85, 120.
6. (a) Shah, N.; Scanlan, T. S. Bioorg. Med. Chem. Lett.
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Santoro, J.; Sitlani, A.; Wang, C.; Williamson, J.; Miller,
D. K.; Yamin, T. D.; Thompson, C. M.; O’Neill, A.;
Zaller, D.; Forrest, M. J.; Carballo-Jane, E.; Luell, S.
Bioorg. Med. Chem. Lett. 2005, 15, 2163.
7. Kumar, V.; Bell, M. R.; Wetzel, J. R.; Herrmann, J. L.;
McGarry, R.; Schane, H. P.; Winneker, R. C.; Snyder, B.
W.; Anzalone, A. J. J. Med. Chem. 1993, 36, 3278.
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D. C.; Samreth, S.; Schuber, F. J.; Renaut, P. P. J. Med.
Chem. 1996, 39, 2302; (b) Pfau, M.; Revial, G.; Guingand,
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Compound 26 was obtained with an ee of 96% (chiral
HPLC analysis) which is consistent with the ee of >95%
for diketone 23 reported in Ref. 8a.
however, as compounds with this group showed rapid
microsomal clearance across species, most importantly
human microsomes.16 Although based on only three
examples (29, 44, 78), it also appeared that the tert-butyl
substituent on the benzenesulfonamide was detrimental
to brain penetration in the rat, possibly due to the molec-
ular size. It can be noted that the compounds with the best
in vivo pharmacokinetic profile (e.g., 43 and 45) have
modest GR functional activity relative to other ana-
logues; hence further optimization of the series is ongoing
in an attempt to improve this situation. Results of these
efforts, and pharmacodynamic testing, will be reported
in due course.
Acknowledgment
We thank Dr. Alec Oxford for his expert advice and
encouragement during the course of this work.
9. Zayia, G. H. Org. Lett. 1999, 1, 989.
10. Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505,
The ee of 35 obtained by this procedure was >98% (chiral
HPLC analysis) which is consistent with the reported
value of 97% ee..
11. The optical purity of final compounds 38–57 and 61–79
was >98% ee on the basis of the ee of the starting ester 35
(Ref. 10). Intermediate 37 (Z = tert-butyl) had an ee of
99% (chiral hplc) confirming that the chiral integrity of the
system was maintained.
References and notes
1. Mohler, M. L.; He, Y.; Wu, Z.; Hong, S.-S.; Miller, D. D.
Expert Opin. Ther. Patents 2007, 17, 59.
2. Clark, R. D.; Ray, N. C.; Blaney, P.; Crackett, P. H.;
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Lockey, P. M.; Devos, R.; Wong, M.; White, A.; Belanoff,
J. K. Bioorg. Med. Chem. Lett. 2007, 17, 5704, Homochi-
ral compounds in the current manuscript have the
indicated absolute stereochemistry. Where absolute ste-
reochemistry is not shown, compounds are racemic.
3. (a) Teutsch, G.; Ojasoo, T.; Raynaud, J. P. J. Steroid
Biochem. 1988, 31, 549; (b) Teutsch, G.; Gaillard-Mogui-
lewsky, M.; Lemoine, G.; Nique, F.; Philibert, D. Biochem.
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Gaillard-Moguilewsky, M.; Nedelec, F.; Tournemine, C.;
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4. Flores, B. H.; Kenna, H.; Keller, J.; Solvason, H. B.;
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5. (a) Fried, J. H.; Mrozik, H.; Arth, G. E.; Bry, T. S.;
Steinberg, N. G.; Tishler, M.; Hirschmann, R.; Steelman,
S. L. J. Am. Chem. Soc. 1963, 85, 236; (b) Hirschmann, R.;
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13. Estrogen receptor: [3H]estradiol, Pan Vera 26467A ERa;
androgen receptor: [3H]dihydrotesterone, Pan Vera 24938
AR; mineralocorticoid receptor: [3H]aldosterone, Sf9 cells/
recombinant MR; progesterone receptor: [3H]progester-
one, Pan Vera 24900 PR.
14. The bridgehead methyl analogue corresponding to 1 had a
Ki of >10 lM in GR binding (unpublished results).
15. Methoxyethyl ethers (rat F%): 50 (8), 52 (0), 55 (2);
amines: 61 (0), 62 (5), 66 (0), 69 (0), 71 (4), 74 (2).
16. For example, methyl ether 43 showed 57% remaining after
a 30 min incubation with human microsomes, compared
to 7% remaining for the corresponding methoxyethyl ether
51.