P.-Y. Michellys et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4071–4075
Table 2. In vitro evaluation of RXR modulators (CV-1 cells)a
4075
Entries
Compds
RXRa
Agonist Eff
RXRa
Agonist EC50
RXRa
Antagonist Eff
RXRa
Antagonist IC50
RXRa/PPARg
Agonist Eff (EC50
RXRa/PPARg
RARg
Agonist Syn.
)
Agonist (EC50
)
1
2
3
4
5
6
7
8
1
2
22
23a
23b
24
34a
34b
34c
34d
34e
34f
42a
42b
42c
56
75ꢂ5
17ꢂ3
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
92ꢂ15
NC
NC
NC
NC
12
161ꢂ25
54ꢂ12
47ꢂ15
63ꢂ18
30ꢂ11
51ꢂ14
46ꢂ17
36ꢂ9
18.6ꢂ5.1
8.6ꢂ3.2
4.1ꢂ2.2
6.4ꢂ5.3
12.2ꢂ5.0
2.7ꢂ1.9
0.4ꢂ0.2
0.8ꢂ0.5
4.7ꢂ2.4
2.7ꢂ1.2
7.4ꢂ5.6
1.3ꢂ1.0
0.7ꢂ0.4
2.7ꢂ1.9
7.4ꢂ4.3
16.3ꢂ16.3
15.1ꢂ9.4
6.9
1.9
1.5
1.8
1.5
1.5
1.5
1.6
1.4
0.8
1.2
1.1
2.8
1.4
1.2
1.0
1.0
4
84ꢂ12
92ꢂ10
87ꢂ8
6.0ꢂ2.1
4.7ꢂ1.6
6.8ꢂ2.3
7.2ꢂ2.5
13.7ꢂ3.0
3.1ꢂ1.0
3.9ꢂ1.1
1.9ꢂ0.5
4.6ꢂ1.5
3.6ꢂ1.5
2.2ꢂ1.2
5.3ꢂ2.0
5.1ꢂ2.2
4.0ꢂ1.2
57.9ꢂ8.3
10.7ꢂ6.4
1
2
1
2
1
1
3
2
92ꢂ11
90ꢂ11
91ꢂ9
91ꢂ11
91ꢂ14
92ꢂ9
9
15ꢂ5
10
11
12
13
14
15
16
17
40ꢂ11
37ꢂ18
32ꢂ8
3
2
89ꢂ6
94ꢂ13
39ꢂ8
44ꢂ13
99ꢂ13
59ꢂ11
71ꢂ14
78ꢂ12
29ꢂ11
3
1
5
5
91ꢂ12
93ꢂ14
83ꢂ15
80ꢂ11
57
aEfficacy for RXRa activity was measured against LGD1069.6 RXR/PPARg synergy mode calculated using 100 nM BRL49653, efficacy relative to
BRL49653. RXR/RAR synergy calculated using 3 nM TTNPB, fold elevation over DMSO background7 (all data shown in nM).
Table 3. Oral exposure study of selected RXR modulators in male ICR mousea
Compd
Oral AUC (0–8 h)
(mg ꢃ h/mL)
Tmax (h)
Cmax
(mg/mL)
(mM)
3
3.8ꢂ1.20
17.7ꢂ4.95
15.17ꢂ2.97
14.41ꢂ3.35
1
3
1
1
0.76ꢂ0.46
3.69ꢂ1.89
4.14ꢂ0.51
4.43ꢂ2.82
1.81ꢂ1.09
8.41ꢂ4.31
9.31ꢂ1.15
10.24ꢂ6.52
23a
34a
42a
aDose formulation of the free acid in CMC/SLS/Povidone (30 mg/kg). Timepoints: 1, 3, and 8 h (serial sacrifice, n=3/timepoint).
2. (a) Schulman, I. G.; Crombie, D.; Bissonnette, R. P.;
Cesario, R.; Roegner, K.; Shao, G.; Heyman, R. A. Handbook
of Experimental Pharmacology; Springer: Berlin, 1999; Vol.
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H. Horm. Res. 2001, 55, 3. (c) Mukherkjee, R.; Davies, P. J. A.;
Crombie, D. L.; Bischoff, E. D.; Cesario, R. M.; Jow, L.;
Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nazdan,
A. M.; Paterniti, J. R.; Heyman, R. A. Nature 1997, 386, 407.
3. Michellys, P. Y.; Ardecky, R. J.; Chen, J. H.; Crombie,
D. L.; Etgen, G.; Faul, M.; Faulkner, A. L.; Grese, T. A.;
Heyman, R. A.; Karanewsky, D. S.; Klausing, K.; Leibowitz,
M. D.; Liu, S.; Mais, D. A.; Mapes, C. M.; Marschke, K.;
Reifel-Miller, A.; Ogilvie, K. M.; Rungta, D.; Thompson,
A. W.; Tyhonas, J. S.; Boehm, M. F. J. Med. Chem. 2003, 46,
2683.
mM). All the compounds displayed in Table 2 show a
dramatic increase in exposure (>3 times) and compound
20a has a longer half-life (3 h instead of 1 h for 3).
In conclusion, we have expediently synthesized a new
series of RXR-selective modulators possessing a fluori-
nated trienoic moiety or various fluorinated, aromatic
or heteroaromatic-substituted core ring systems from
inexpensive starting materials. All the compounds
selectively bind with high affinity to RXRs versus
RARs. They also possess little or no RXR/RAR
synergy (<2-fold) and activate the RXR/PPARg het-
erodimer when used in combination with a PPARg
agonist (BRL49653). The PK profiles (AUC calcula-
tion) for a subset of this new series of compounds have
been examined in IRC mice. The exposure data pre-
sented in Table 3 show a dramatic exposure increase
compared to our lead compound 3.
4. Zhang, L.; Nazdan, A. M.; Heyman, R. A.; Love, D. L.;
Mais, D. E.; Croston, G. E.; Lamph, W. W.; Boehm, M. F. J.
Med. Chem. 1996, 39, 2659.
5. Carini, D. J.; Chiu, A. T.; Wong, P. C.; Johnson, A. L.;
Wexler, R. R.; Timmermans, L. Bioorg. Med. Chem. Lett.
1993, 3, 895.
6. Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.;
Mais, D. A.; Berger, E.; Suto, C. M.; Goldman, M. E.; Hey-
man, R. A. J. Med. Chem. 1994, 37, 2930.
References and Notes
7. Michellys, P.-Y.; Ardecky, R. J.; Chen, J.-H.; D’Arrigo, J.;
Grese, T. A.; Karanewsky, D. S.; Leibowitz, M. D.; Liu, S.;
Mais, D. A.; Mapes, C. M.; Montrose-Rafizadeh, C.; Ogilvie,
K. M.; Reifel-Miller, A.; Rungta, D.; Thompson, A. W.;
Tyhonas, J. S.; Boehm, M. F. J. Med. Chem. 2003, 46, 4087.
1. (a) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke,
B. R. J. Med. Chem. 2000, 44, 527 and references therein. (b)
Lehnard, J. M. Recept. Channels 2001, 7, 249. (c) Jones, A. B.
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