2804
S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
We also investigated the effect of substituting indole for
phenyl on the western side of the triazole. These com-
pounds were prepared by Method D (Scheme 5) or
Method E, (Scheme 6). Data for compounds in this ser-
ies are presented in Table 3.
References and notes
1. For recent reviews see: Tomlinson, J. W.; Walker, E. A.;
Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper, M. S.;
Hewison, M.; Stewart, P. M. Endocr. Rev. 2004, 25, 831;
Seckl, J. R.; Walker, B. R. Trends Endocrinol. Metab. 2004,
15, 418; Walker, E. A.; Stewart, P. M. Trends Endocrinol.
Metab. 2003, 14, 334; Walker, B. R.; Seckl, J. R. Expert
Opin. Ther. Targets 2003, 7, 771.
2. (a) Reaven, G. Circulation 2002, 106, 286; (b) Seckl, J. R.;
Walker, B. R. Trends Endocrinol. Metab. 2004, 15, 418,
(and references therein).
3. (a) Kotelevtsev, Y. V.; Brown, R. W.; Fleming, S.;
Edwards, C. R.; Seckl, R. J.; Mullins, J. J. J. Clin. Invest.
1999, 103, 683; (b) Wilson, R. C.; Harbison, M. D.;
Krozowski, Z. S.; Funder, J. W.; Shackleton, C. H.;
Hanauske-Abel, H. M.; Wei, J. Q.; Hertecant, J.; Moran,
A.; Neiberger, I. E. Clin. Endocrinol. Metab. 1995, 80,
3145; (c) Monder, C.; Stewart, P. M.; Lakshimi, V.;
Valentino, R.; Burt, D.; Edwards, C. R. Endocrinolgy
1989, 125, 1046.
4. (a) Masuzaki, H.; Paterson, J. M.; Shinyama, H.; Morton,
N. M.; Mullins, J. J.; Seckl, R. J.; Flier, F. S. Science 2001,
294, 2166; (b) Masuzaki, H.; Yamamoto, H.; Kenyon, C. J.;
Elmquist, J. K.; Morton, N. M.; Paterson, J. M.; Shinyama,
H.; Sharp, M. G. F.; Fleming, S.; Mullins, J. J.; Seckl, R. J.;
Flier, F. S. J. Clin. Invest. 2003, 112, 83; (c) Paterson, J. M.;
Morton, N. M.; Fievet, C.; Kenyon, C. J.; Holmes, M. C.;
Staels, B.; Seckl, R. J.; Mullins, J. J. J. Proc. Natl. Acad.
Sci. 2004, 101, 7088.
The N-methyl indole series (33–35 compared with 36–
37) reiterates what was observed with the bis-phenyl
compounds in that substitution on the phenyl ring is
needed for potency. The indoles differ in that a para sub-
stituent (p-OH in 33) rather than just the ortho, confers
very good activity, a phenomenon which was observed
with an earlier set of analogs we examined. In addition,
the potency is substantially lowered if connection to the
triazole is on C5 of the indole (37).
The final area that we explored was replacing the indole
group with a naphthylene. These triazoles were prepared
using Methods A, B and C (Schemes 2–4). Table 4 dis-
plays the observed SAR for these compounds.
The potency of compound 38, the 7-chloro-1-methoxy
naphthyl triazole surpasses all the others in the bis-aryl
series with its good PD activity extending out to 16 h but
seems to have rather specific requirements for maintain-
ing this activity. The 16 h potency is reduced somewhat
(39) when the chloro substituent is absent. A much lar-
ger drop in mouse PD activity is seen with the chloro at
the 4-position (47), when o-SO2Me replaces the o-CF3
on the phenyl ring (48) or when the methoxy is replaced
by a hydroxyl group (45); human potency is also lower
with (45). PD potency is generally lower when just a sin-
gle substituent (1-fluoro, 1-N-methylamino, 7-methyl or
3-chloro) is present on the naphthyl ring. Finally, mouse
activity drops significantly and is reflected in poor PD as
well if the connection to the triazole is on C1 of the
naphthyl (49).
5. For a review see: White, P. C.; Mune, T.; Agarwal, A. K.
Endocr. Rev. 1997, 18, 135.
6. Hermanowski-Vosatka, A.; Balkovec, J. M.; Cheng, K.;
Chen, H. Y.; Hernandez, M.; Koo, G. C.; LeGrand, C.
B.; Li, Z.; Metzger, J. M.; Mundt, S. S.; Noonan, H.;
Nunes, C. N.; Olson, S. H.; Pikounis, B.; Ren, N.;
Robertson, N.; Schaeffer, J. M.; Shah, K.; Springer, M.;
Strack, A. M.; Strowski, M.; Wu, K.; Wu, T.; Xiao, J.;
Zhang, B. B.; Wright, S. D.; Thieringer, R. J. Exp. Med.
2005, 202, 517.
7. Olson, S. H.; Aster, S. D.; Brown, K.; Carbin, L.; Graham,
D. W.; Hermanowski-Vosatka, A.; LeGrand, C. B.;
Mundt, S. S.; Robbins, M.; Schaeffer, J. M.; Slossberg, L.
H.; Szymonifka, M. J.; Thieringer, R.; Wright, S. D.;
Balkovec, J. M. Bioorg. Med. Lett. 2005, 12, 4359.
8. For details of enzymatic assays see Ref. 6. The pharmaco-
dynamic (PD) assay was performed as follows. The test
compound was dosed orally at 10 mg/kg, and after a
In summary, we have identified several new classes of
potent and selective mouse and human 11b-HSD1
inhibitors. Potency of relatively simple bis-phenyl tria-
zoles has been enhanced by the inclusion of various o-
halogens and the o-CF3 group. Potency can be main-
tained by incorporating a 4- or 5-carbon chain in the
4-position. Good activity is observed with an N-methyl
indole replacing one of phenyls and para substitution
on the 2nd phenyl ring is well tolerated. Finally, ex-
tended PD potency out to 16 h is seen with a 7-chloro-
1-methoxy naphthyl group replacing one of the phenyls.
3
prescribed time interval, H-cortisone was injected intrave-
nously via the tail vein. After 2 min, blood was collected by
cardiac puncture. Steroids were extracted from the serum
and analyzed by HPLC. The relative levels of H-cortisone
3
and 3H-cortisol were measured and a percent inhibition was
calculated.