Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Article abstract of DOI:10.1016/j.bmcl.2011.05.101

A series of pyridyl amide/sulfonamide inhibitors of 11β-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.

Full text of DOI:10.1016/j.bmcl.2011.05.101

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4146–4149
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of
human 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD-1)
⇑
Haixia Wang, Jeffrey A. Robl , Lawrence G. Hamann, Ligaya Simpkins, Rajasree Golla, Yi-Xin Li,
Ramakrishna Seethala, Tatyana Zvyaga, David A. Gordon, James J. Li
Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyridyl amide/sulfonamide inhibitors of 11b-HSD-1 were modified to incorporate a novel
1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with
a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent
and metabolically stable inhibitor of the enzyme.
Received 2 May 2011
Revised 24 May 2011
Accepted 25 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Type 2 diabetes
11b-HSD-1 inhibitors
Triazolopyridine
PXR
A primary pathophysiological defect in type 2 diabetes is resis-
tance to the action of insulin in the liver, adipose tissue and skele-
tal muscle. Glucocorticoids play an important role in the regulation
of these processes. In the liver, glucocorticoids directly upregulate
the rate limiting enzymes in both the glycogenolysis and gluconeo-
genesis pathways thereby providing a mechanism for increased
hepatic glucose output. In the adipose tissue, glucocorticoids dam-
pen insulin signaling thereby reducing the ability of insulin to
stimulate glucose uptake. Excess glucocorticoid tone in these tis-
sues represents an assault on glucose homeostasis, leading to
hyperglycemia and eventually type 2 diabetes, a major risk factor
for cardiovascular disease.1 For example, it is well known that an
excess of glucocorticoid tone via secretion from the adrenal gland,
such as that observed in Cushing’s Disease, leads to major pertur-
bations in glucose and lipid metabolism including hyperglycemia,
type 2 diabetes and accelerated cardiovascular disease. This has
led to the hypothesis that lowering the glucocorticoid tone in
patients afflicted with type 2 diabetes could be an efficacious ther-
apeutic strategy that is relevant to the underlying pathophysiology
of this disease.
production of cortisol represents a pathway by which glucocorti-
coid tone may be modulated in tissues. As a result, numerous
groups have reported generating highly potent and selective 11b-
HSD-1 inhibitors,3 with several compounds having been advanced
to clinical trials.4
Recently we published our efforts on the exploration and opti-
mization of a series of pyridyl amides5 and sulfonamides6 which
afforded highly potent and selective inhibitors of human 11b-
HSD-1 (represented by structure 1, Fig. 1). Compound 2 proved
to be one of the most potent analogs in this series, affording sin-
gle-digit nanomolar activity versus the enzyme. From X-ray crys-
tallographic structures of these inhibitors bound to human 11b-
HSD-1, it was determined that the amide carbonyl served as the
critical hydrogen bonding pharmacophore to the Ser170 and
Tyr183 residues within the enzyme’s active site. In an extension
of this work, we focused our attention on finding novel and pro-
prietary core structures which may serve as suitable hydrogen
bonding surrogates for the amide carbonyl pharmacophore. Incor-
poration of various heterocyclic replacements led to the identifica-
tion of the 1,2,4-triazolopyridine (TZP) core (as depicted in
structure 3) as a highly suitable replacement.7 While potent
in vitro, compound 3 suffered from extensive metabolic degrada-
tion in liver microsomal preparations, in part via oxidation of the
benzylic and sulfide moieties. Replacement of the sulfur atom with
oxygen (compound 4) incrementally enhanced oxidative stability
but attenuated potency. Gratifyingly, replacement of the cyclo-
hexyl group in 4 with cycloheptyl (affording 5) restored in vitro po-
tency. Based on the potential of this lead, a more extensive
structure–activity relationship (SAR) study was undertaken in this
11b-Hydroxysteroid dehydrogenase- type 1 (11b-HSD-1) is an
enzyme that catalyzes the conversion of inert cortisone to the ac-
tive glucocorticoid hormone cortisol and is expressed at high levels
in the liver and adipose tissue, two tissues of primary importance
to metabolic diseases.2 As such, 11b-HSD-1-mediated in situ
⇑
Corresponding author. Tel.: +1 609 818 5048; fax: +1 609 818 3550.
E-mail address: Jeffrey.robl@bms.com (J.A. Robl).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.101

H. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4146–4149
4147
yields. A variety of methods were employed to effect cyclization
of 7a–e to the corresponding TZP intermediates/final products,
the most effective of which was treatment with PPh3Cl2 and
i-Pr2NEt or Et3N in methylene chloride. Reduction of 8b was ef-
fected via catalytic hydrogenation and the intermediate amine
subject to sulfonylation to afford 15. Desilylation of 8a afforded
the versatile intermediate 9 which could then be further function-
alized according to the methods in Scheme 1, affording the inhib-
itors listed in Table 1.
X
O
Cl
S
O
Y
N
N
Z
N
N
Me
Cl
1
Me
X = H, halogen
Y-Z = 0-3 atom linkers
2
h-11β-HSD-1 IC50 = 7.2 nM
Cl
Cl
N
N
N
N
Table 1 predominantly focuses on the effect of the linker (X–Y)
on human 11b-HSD-1 inhibitory activity. Overall, the SAR appears
to be more empirical than predictable. Highest potency was
achieved when X–Y is OCH2 (5) or SCH2 (16). Interestingly, simple
transposition of the OCH2 linker in 5 to give the CH2O linked 10 re-
sulted in a significant attenuation in potency, while the longer (11)
and shorter (12 and 18) oxygen linked analogs still retained rea-
sonable activity. Surprisingly, although the ‘three atom linker’ sul-
fonamide 14 was very potent versus the enzyme, the related ‘two
atom’ sulfone (13) and sulfonamide (15) were weakly active. The
significant variation in activity with respect to linker identity sug-
gests strict structural requirements at this position of the molecule.
Of high interest in this data set were the direct oxygen linkers
(X–Y = O, compounds 12 and 18). While not the most potent in
the series, they presented more favorable metabolic stability pro-
files due to the absence of benzylic methylene groups and there-
fore represented preferable appendages for additional exploration
in the series (see Table 2 for microsomal stability of 18).
Extending the findings above, we embarked on a detailed explo-
ration of replacements for the cycloheptyl appendage found in
compound 18. The synthesis of these derivatives is depicted gener-
ically in Scheme 2. A variety of commercially available or readily
synthesized carboxylic acids 19 were coupled with hydrazine 6e
to afford hydrazide 20 in generally good yields (31–99%). Cycliza-
tion using one of the three methods (d, e or f) yielded the desired
inhibitors 18–23, 25, 26, 28, 29, 31, 32, 35 and 36. Compounds 24,
S
N
O
N
Cl
Cl
3
4
h-11β-HSD-1 IC50 = 11 nM
h-11β-HSD-1 IC50 = 143 nM
Cl
N
N
5
3
N
h-11β-HSD-1 IC50 = 11 nM
O
8
Cl
Figure 1. Generation of 1,2,4-trizolopyridine 11b-HSD-1 inhibitors based on
pyridyl amide chemotype 1.
series to enhance in vitro potency while attenuating potential
development liabilities (e.g. metabolic stability, solubility, PXR
induction, etc.). Using compound 5 as a starting point, studies were
undertaken to independently vary the substituents at both the C-3
(i.e., cycloheptyl) and C-8 (i.e., aryl-linker) position of the TZP core.
Initial work was focused on the effect of linker variation be-
tween the TZP core and the distal aromatic group. The synthesis
of these compounds is depicted in Scheme 1. The requisite pyridyl
hydrazines 6a–e were generated from the commercially available
chlorides or fluorides shown below. Cycloheptane carboxylic acid
was coupled with various 3-substituted 2-pyridyl hydrazines to af-
ford the corresponding acyl hydrazides 7a–e in typically high
F
F
HO
b
a
HO
N
N
F
O2N
N
c
NHNH2
N
G
H
N
N
N
HN
d
e
G
O
G
N
CO2H
N
6a (G = TBDMSOCH2)
6b (G = O2N)
6c (G = 2,6-dichlorobenzyloxy)
6d (G = 2,6-dichlorophenoxy)
6e (G = 3-chloro-2-methyphenoxy)
8a (G = TBDMSOCH2)
8b (G = O2N)
10 (G = 2,6-dichlorobenzyloxy)
12 (G = 2,6-dichlorophenoxy)
18 (G = 3-chloro-2-methyphenoxy)
7a-e
5
i
for 8a,
step h
N
N
for 8b
steps
f, g
k
l
13
16
N
HO
j
9
15
11
m, n
14, 17
Scheme 1. Reagents and conditions: (a) For compounds 6d and 6e: substituted phenylboronic acid, Cu(OAc)2, pyridine, 4A mol. sieves, CH2Cl2, rt, 14 h (6% for 6d, 77% for 6e),
then excess anhydrous H2NNH2, dioxane, reflux (ꢀ100%); For compound 6c: 2,6-dichlorobenzyl bromide, K2CO3, acetone, rt (ꢀ100%), then 10 equiv. anhydrous H2NNH2,
dioxane, reflux (96%); (b) For compound 6a: TBDMSCl, imidazole, CH2Cl2 (ꢀ100%), then 10 equiv anhydrous H2NNH2, dioxane, reflux (32%); (c) For compound 6b: 5 equiv
anhydrous H2NNH2, EtOH, rt, ꢀ100%; (d) N-methyl morpholine, i-BuOCOCl, 0 °C, then 6a–e, 31–94%; (e) PPh3Cl2, i-Pr2NEt or Et3N, 54–92%; (f) 15 psi H2/Pd–C, 45%; (g) 2,6-
dichlorophenylsulfonyl chloride, polyvinyl pyridine, 13%; (h) (n-Bu)4NF, THF, rt, 95%; (i) 2,6-dichlorophenol, Ph3P, DIAD, 89%; (j) NaH, 2,6-dichlorobenzyl bromide, 56%; (k),
SOCl2, then 2,6-dichlorothiophenol, i-Pr2NEt, 91%; (l) m-ClPhCO3H, CH2Cl2, rt, 48%; (m) (i) CH3SO2Cl, Et3N, CH2Cl2, 0 °C to rt; (ii) NaN3, DMF, 50 °C; (iii) polymer bound PPh3,
THF, 50 °C, 80% for three steps; (n) 2,6-dichlorophenylsulfonyl chloride or 2-chloro-3-methylphenylsulfonyl chloride, Et3N, 35–41%.

4148
H. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4146–4149
Table 1
Table 2
SAR of cycloheptyl substituted TZP analogs 5 and 10–18
Structure–activity relationship regarding variation of the R substituent of the 1,2,4-
trizolopyridine ring
N
N
N
N
Me
Aryl
Y
X
N
Cl
O
N
R
a
Compd
Aryl
X–Y
IC50 (nM)
a
Compd
R
IC50 (nM)
% Remainingb
5
10
11
12
13
14
15
16
17
18
2,6-diClPh
2,6-diClPh
2,6-diClPh
2,6-diClPh
2,6-diClPh
2,6-diClPh
2,6-diClPh
2,6-diClPh
OCH2
CH2O
11
578
34
36
2962
17
8778
2.8
12
Hu
23
Mu
Hu
Mu
53
57
<1
CH2OCH2
O
SO2CH2
SO2NHCH2
SO2NH
SCH2
18
21
22
4105
167
327
64
69
<1
3.7
5.5
2-Me,3-ClPh
2-Me,3-ClPh
SO2NHCH2
O
MeO
23
OMe
a
IC50’s refer to biochemical human 11b-HSD-1 assay data8.
23
5.6
1214
19
13
27, 30, 33, 34, 37 and 38 were prepared through subsequent trans-
formations of the initially formed cyclization products.9
24
25
8.2
4313
25
53
21
13
HO
As mentioned previously, the majority of the derivatives suf-
fered from poor microsomal stability and thus was anticipated to
exhibit little/modest exposure in our in vivo models upon oral dos-
ing. Metabolic identification studies on compound 18 clearly indi-
cated that the cycloheptyl ring (and not the disubstituted aryl
ether) was highly subject to oxidative metabolism in human and
mouse liver microsomes. As a result, we sought to simultaneously
maintain/enhance in vitro potency while modulating metabolism
at this position by either blocking the sites of metabolism or incor-
porating polar substitutents, making the compounds poorer sub-
strates for the metabolizing enzymes. Susceptibility to oxidative
metabolism was measured via incubation of compound in liver
microsomes and the percent compound remaining was deter-
mined. Listed in Table 2 is a limited but representative set of com-
pounds generated in this assessment.
As compared to lead 18, increasing lipophilicity, especially with
quaternary substitution at the carbon directly attached to the TZP
core, had a positive impact on in vitro potency (compare com-
pound 18 vs 21–24). Though both 21 and 25 contain relatively
large lipophilic groups, the sub-optimal methylene spacer present
in 25 likely contributed to the >40-fold reduction in the IC50 versus
21. The highly lipophilic nature of these groups likely contributes
to the generally poor metabolic stability of these compounds.
Though quite stable metabolically, presumably due to blocking of
metabolism by the fluorine groups, compound 26 exhibited poor
activity as a result of minimal hydrophobic space-filling in the en-
zyme binding pocket. Introduction of polar functionalities
(i.e., examples 27–31) had a dramatic effect on enhancing meta-
bolic stability towards human and mouse microsomes but the
modifications were poorly tolerated by 11b-HSD-1. Not surpris-
ingly, incorporation of a protonatable amine group (examples 32
and 33) resulted in poor enzyme activity but excellent metabolic
stability. A nearly direct comparison of 21 versus the related ami-
no-substituted derivative 32 illustrates the magnitude of the effect.
With these observations in mind, we turned our attention to incor-
poration of substituted bi- and polycyclic groups at R. Hydroxy-
substituted cycloheptyl 34 and adamantyl 35 analogs showed mar-
ginally better metabolic stability (human) but at the expense of
in vitro potency. In contrast, introduction of the 2,2,2-bicyclooc-
tane moiety proved to be a superior scaffold for compound optimi-
zation. While the methoxy-substituted analog 36 was sub-optimal
with respect to potency (and incidentally subject to bioconversion
to 38 via oxidation of the methoxy group), the corresponding flu-
oro-derivative 37 afforded superior potency. Finally, introduction
of hydroxyl at the bridgehead position (38) proved to be an ideal
163
>10,000
F
26
27
939
367
>10,000
>10,000
100
99
87
97
F
OH
Me
28
29
7804
544
NTc
NT
NT
O
>10,000
100
100
O
N
NH
30
14,030
>10,000
95
99
O
31
32
33
48,240
16,060
1298
>10,000
NT
87
90
96
NT
Ac
100
NT
N
21,130
NH2
HO
34
35
197
64
>10,000
NT
81
69
43
53
OH
36
37
38
72
8.5
12
6851
4155
1026
87
70
62
96
OMe
F
76
100
OH
a
IC50’s refer to biochemical human (Hu) or mouse (Mu) 11b-HSD-1 assay data.
Represents % compound remaining in human or mouse liver microsomes after a
10 min incubation.
b
c
Not tested.
combination of potency and in vitro metabolic stability in this
set of compounds.
Compound 38 also proved to be superior for other aspects of
profiling as well. Pregnane-X receptor (PXR) transactivation has
been observed for many compounds in this chemotype, as well
as for compounds from other laboratories targeting this enzyme.10

H. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4146–4149
4149
R/R1
H
N
Me
HN
a, b, or c
NHNH2
R/R1
19
Cl
O
O
N
HO
Me
Cl
O
O
N
20
6e
N
Me
N
N
Me
N
Ref. 9
Cl
O
R
d, e or f
N
Cl
O
R/R1
N
(conversion
of R1 to R)
R: 18-23, 25, 26, 28, 29, 31,
32, 35, 36
24, 27, 30, 33, 34, 37, 38
R1: Precursors for 24, 27, 30,
33, 34, 37, 38
Scheme 2. Reagents and conditions: (a) N-methyl morpholine, i-BuOCOCl, 0 °C; (b) (COCl)2; (c) HOBT, EDAC, rt, 31–99%; (d) PPh3Cl2, i-Pr2NEt, CH2Cl2, rt; (e) HOAc, EtOH,
reflux; (f) HOAc, trifluorotoluene, W, 180 °C, 71–95%.
l
3. For recent reviews on the design of inhibitors for this target, see: (a) Fotsch, C.;
Wang, M. J. Med. Chem. 2008, 51, 4851; (b) Morgan, S. A.; Tomlinson, J. W. Exp.
Opin. Invest. Drugs 2010, 19, 1067.
Indeed, this liability seemed to be evident with most, if not all, of
the chemotypes explored in our chemical program. Since activa-
tion of PXR in vivo is a liability risk for CYP450 induction and
increased potential for drug–drug interactions, removing this off-
target activity was a constant focus of the program. Compounds
containing non-polar highly lipophilic ‘R’ groups such as 18, 21–
25, and 37 exhibited partial to full activation of PXR with EC50’s
4. Several companies have advanced compounds into clinical trials: (a) for AMG-
221 see: (a) Veniant, M. M.; Hale, C.; Hungate, R. W.; Gahm, K.; Emery, M. G.;
Jona, J.; Joseph, S.; Adams, J.; Hague, A.; Moniz, G.; Zhang, J.; Bartberger, M. D.;
Li, V.; Syed, R.; Jordan, S.; Komorowski, R.; Chen, M. M.; Cupples, R.; Kim, K. W.;
St. Jean, D. J., Jr.; Johannsson, L.; Henriksson, M. A.; Williams, M.; Vallgarda, J.;
Fotsch, C.; Wang, M. J. Med. Chem. 2010, 53, 4481; for PF-915275 see: (b) Siu,
M.; Johnson, T. O.; Wang, Y.; Nair, S. K.; Taylor, W. D.; Cripps, S. J.; Matthews, J.
J.; Edwards, M. P.; Pauly, T. A.; Ermolieff, J.; Castro, A.; Hosea, N. A.; LaPaglia, A.;
Fanjul, A. N.; Vogel, J. E. Bioorg. Med. Chem. Lett. 2009, 19, 3493; for INCB13739
see: (c) Rosenstock, J.; Banarer, S.; Fonseca, V. A.; Inzucchi, S. E.; Sun, W.; Yao,
W.; Hollis, G.; Flores, R.; Levy, R.; Williams, W.; Seckl, J. R.; Huber, R. Diabetes
Care 2010, 33, 1516; for MK-0916 and MK-0736 see, (d) Shah, S.;
Hermanowski-Vosatka, A.; Gibson, K.; Ruck, R. A.; Jia, G.; Zhang, J.; Hwang, P.
M. T.; Ryan, N. W.; Langdon, R. B.; Feig, P. U. J. Am. Soc. Hypertens. 2011, 5, 166.
5. Wang, H.; Ruan, Z.; Li, J. L.; Simpkins, L. M.; Smirk, R. A.; Wu, S. C.; Hutchins, R.
D.; Nirschl, D. S.; Van Kirk, K.; Cooper, C. B.; Sutton, J. C.; Ma, Z.; Golla, R.;
Seethala, R.; Salyan, M. E. K.; Nayeem, A.; Krystek, S. R., Jr.; Sheriff, S.; Camac, D.
M.; Morin, P. E.; Carpenter, B.; Robl, J. A.; Zahler, R.; Gordon, D. A.; Hamann, L.
G. Bioorg. Med. Chem. Lett. 2008, 18, 3168.
in the 0.15–3
activation of this receptor (EC50 >50
l
M range. In contrast, compound 38 exhibited weak
M), suggesting that critical
l
placement of the polar hydroxyl group significantly attenuated
activity against PXR. Beneficially, compound 38 also exhibited
marginal but enhanced solubility (ꢀ11
l
g/mL, pH 7.4) as com-
pared to lipophilic analogs such as 21 and 37 (ꢀ1
lg/mL, pH 7.4).
Other in vitro development properties (CYP inhibition, ion channel
activity, cytotoxicity, etc.) were also favorable for 38.
Though favorable in many aspects, two significant properties
proved difficult to address in this series. First, many of the com-
pounds exhibited marginal selectivity against the human
11b-HSD-2 enzyme. Selectivity is a critical component in order to
minimize the potential for deleterious side-effects associated with
11b-HSD-2 inhibition (e.g., hypertension and hypokalemia). While
compound 38 exhibited ꢀ200-fold selectivity for h-11b-HSD-1
6. Wang, H.; Li, J. L.; Simpkins, L. M.; Sutton, J. C.; Wu, S. C.; Smirk, R. A.; Yoon, D.;
Ruan, Z.; Cooper, C. B.; Van Kirk, K.; Hutchins, R. D.; Li, C.; Ma, P.; Seethala, R.;
Golla, R.; Nayeem, A.; Krystek, Jr., S. R.; Gordon, D. A.; Robl, J. A.; Hamann, L. G.
Abstract of Papers, 233rd National Meeting of the American Chemical Society:
Chicago, IL, March 2007; MEDI 377.
7. Li, J. J; Hamann, L. G.; Wang, H.: Ruan, Z.; Cooper, C. B.; Li, J.; Robl, J. A. WO2006/
135995 A1, Dec 21, 2006.
8. 11b-HSD1 microsomes isolated from HEK 293 cells over-expressing human
11b-HSD1 were incubated with the substrate cortisone and cofactor NADPH at
room temperature. The reactions were terminated with the addition of a
nonspecific 11b-HSD1 inhibitor (18b-glycyrrhetinic acid). The product, cortisol
was quantified in an immuno-competition SPA wherein the [3H]-cortisol
bound to anti-rabbit antibody yttrium silicate SPA beads coated with
polyclonal anti-cortisol antibody was competed by cortisol produced in the
reaction and the reaction mixture was read in a scintillation plate reader
(TopCount). The IC50 was then determined by amount of cortisol formed from a
cortisol standard curve.
versus h-11b-HSD-2 (IC50 = 2.52 lM), other compounds such as
22 and 37 were less so (ꢀ70-fold). This represented an area for fur-
ther improvement. Additionally, and as a class, the TZP series
exhibited routinely poor mouse in vitro activity. As seen in Table
2, none of the compounds exhibited robust potency for the mouse
enzyme, precluding our ability to assess pharmacological inhibi-
tion in murine in vivo models.
In conclusion, replacement of an amide/sulfonamide pharmaco-
phore in an early lead series with a triazolopyridine group afforded
a novel platform for further SAR exploration. Variation of both the
left and right-hand portions of the lead 5 resulted in a series of
highly potent inhibitors of human 11b-HSD-1. In an attempt to
overcome some of the historical liabilities (poor metabolic stabil-
ity, PXR transactivation, etc.) associated with the drug optimiza-
tion for this target, compound 38 was identified as a highly
advanced lead. Future disclosures in this chemotype will focus on
the further optimization of 38 with the goal to identify a candidate
suitable for in vivo evaluation.
9. Compound 24 was prepared by reduction of the corresponding ketone: NaBH4,
78%; 27 was made from ketone 28: MeMgBr, 62%; 30 was also obtained from
ketone 28: (1) NH2OH.HCl, NaOAc, (2) PhSO2Cl, NaOH, 31% for two steps; 33
was obtained from compound 36: (1) HBr, Ac2O, 3%, (2) NH3/MeOH, lW, 5%; 34
was obtained from the corresponding TBDMS protected alcohol: TBAF, 92%; 37
was synthesized from compound 38: DAST, 53%; 38 was obtained from
compound 36: HBr, Ac2O, 79%.
10. Recent examples of chemotypes with PXR activities include: (a) Zhu, Y.; Olson,
S. H.; Hermanowski-Vosatka, A.; Mundt, S.; Shah, K.; Springer, M.; Thieringer,
R.; Wright, S.; Xiao, J.; Zokian, H.; Balkovec, J. M. Bioorg. Med. Chem. Lett. 2008,
18, 3412; (b) Fotsch, C.; Bartberger, M. D.; Bercot, E. A.; Chen, M.; Cupples, R.;
Emery, M.; Fretland, J.; Guram, A.; Hale, C.; Han, N.; Hickman, D.; Hungate, R.
W.; Hayashi, M.; Komorowski, R.; Liu, Q.; Matsumoto, G.; St Jean, D. J., Jr.; Ursu,
S.; Veniant, M.; Xu, G.; Ye, Q.; Yuan, C.; Zhang, J.; Zhang, X.; Tu, H.; Wang, M. J.
Med. Chem. 2008, 51, 7953; (c) Rew, Y.; McMinn, D. L.; Wang, Z.; He, X.;
Hungate, R. W.; Jaen, J. C.; Sudom, A.; Sun, D.; Tu, H.; Ursu, S.; Villemure, E.;
Walker, N. P. C.; Yan, X.; Ye, Q.; Powers, J. P. Bioorg. Med. Chem. Lett. 2009, 19,
1797.
References and notes
1. Morton, N. M. Mol. Cell. Endocrinol. 2010, 316, 154.
2. (a) Walker, B. R.; Andrew, R. Ann. N.Y. Acad. Sci. 2006, 1083, 165; (b)
Oppermann, U. Endo. Metabol. Immun. Disord.-Drug Targets 2006, 6, 259.