886
Y.-L. Li et al. / Bioorg. Med. Chem. Lett. 16 (2006) 884–886
Table 1. Thyroid hormone receptor binding affinities (IC50) of 1, and
synthetic thyromimetics 2, 3 and 12a–ea
3. (a) Ye, L.; Li, Y.-L.; Mellstro¨m, K.; Bladh, L.-G.; Koehler,
K.; Garg, N.; Garcia Collazo, A. M.; Litten, C.; Husman,
B.; Persson, K.; Ljunggren, J.; Grover, G.; Sleph, P. G.;
George, R.; Malm, J. J. Med. Chem. 2003, 46, 1580; (b)
Grover, G. J.; Mellstro¨m, K.; Ye, L.; Malm, J.; Li, Y.-L.;
Bladh, L.-G.; Sleph, P. G.; Smith, M. A.; George, R.;
Vennstro¨m, B.; Mookhtiar, K.; Horvath, R.; Speelman, J.;
Egan, D.; Baxter, J. D. Proc. Natl. Acad. Sci. U.S.A. 2003,
100, 10067.
b
Compound
hTRa1
IC50
hTRb1
IC50
a1/b1
1
0.24
25
13
0.26
1.1
0.54
14
38
2
3
0.20
140
18
12a
12b
12c
12d
12e
12f
3300
630
14
21
4. (a) Hangeland, J. J.; Doweyko, A. M.; Dejneka, T.;
Friends, T. J.; Devasthale, P.; Mellstro¨m, M.; Sandberg,
240
4.3
33
16
1300
610
47
16
˚
J.; Grynfarb, M.; Sack, J. S.; Einspahr, H.; Fa¨rnegardh,
22
16
M.; Husman, B.; Ljunggren, J.; Koehler, K.; Sheppard, C.;
Malm, J.; Ryono, D. E. Bioorg. Med. Chem. Lett. 2004, 14,
3549; (b) TRb-selectivity within the same range as 3 has
1200
45
a IC50 and EC50 values are expressed as nanomolar and are calculated
means of duplicate runs for 12a–f. Data for 1, 2, and 3 are taken from
Ref. 3a,4a, respectively. These data are intended for comparison with
the new ligands.
b Normalized selectivity: (IC50 hTRa1/(IC50 hTRb1 · 1.7). For an
explanation, see Ref. 3a.
3
0
been disclosed within two other series of R -substituted
thyromimetics. R1-position 6-azauracil derivatives: Dow,
R. L.; Schneider, S. R.; Paight, E. S.; Hank, R. F.; Chaing,
P.; Cornelius, P.; Lee, E.; Newsome, W. P.; Swick, A.;
Spitzer, J.; Hargrove, D. E.; Patterson, T. A.; Pandit, J.;
Chrunyk, B. A.; LeMotte, P. K.; Danley, D. E.; Rosner, M.
H.; Ammirati, M.J.; Simones, S. P.; Schulte, G. K.; Tate, B.
F.; DaSilva-Jardine, P. Bioorg. Med. Chem. Lett. 2003, 13,
379; and the R1-acetoxy derivative GC-24: Borngraeber, S.;
Budny, M. J.; Chiellini, G.; Cunha-Lima, S. T.; Togashi,
M.; Webb, P.; Baxter, J. D.; Scanlan, T. S.; Fletterick, R. J.
Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15358.
and selectivity was found when the amido-function was
substituted with an iso-butyl group (12c), whose TRb-
selectivity is within the same range as 3. Both affinity
and selectivity decreased with larger as well as with
smaller groups.
5. This work was in part based on data disclosed in: PCT
Int. Appl., 86 pp., 2001. Application: WO01/98256.
Priority: GB00/15205. CAN 136:54021. While compiling
this communication, investigators from Bayer AG dis-
closed a number of novel outer ring heterocycle-fused
thyromimetics, carrying indoles or indazoles instead of the
phenolic group in L-T3 in: Haning, H.; Woltering, M.;
Mueller, U.; Schmidt, G.; Schmeck, C.; Voehringer, V.;
Kretschmer, A.; Pernerstorfer, J. Bioorg. Med. Chem.
Lett. 2005, 15, 1835. These ligands were, however, only
moderately TRb-selective, but clearly represent a highly
novel approach.
6. The following procedure was used to calculate the relative
difference in temperature factors for the TRa and TRb
structures (PDB accession codes 1NAV and 1NAX,
respectively). First, the temperature factors for all atoms
within all structurally conserved residues (residue numbers
157–180, 187–198, 207–406 and 211–235, 241–252, 261–
461, for TRa and TRb, respectively) were normalized to
zero for each structure. Then for each structurally con-
served residue in the TRb structure, the average tempera-
ture factor for all the atoms within that residue was
calculated and subtracted from the average temperature
factor in the corresponding residue in TRa. Finally the
temperature factors for all the atoms within the residue in
the TRb structure were set to this difference. These
calculations were performed using a Python script (avail-
able from the authors upon request) using functions from
the BioPython module Bio.PDB (Hamelryck, T., Mander-
ick, B. (2003) PDB parser and structure class implemented
in Python. Bioinformatics, 19, 2308–2310).
In summary, based on a comparison of the X-ray crys-
tallographic structures of TRa1 and TRb1 in complex
with 2, we designed and prepared a number of novel
40-hydroxy bioisosteric thyromimetics. Optimal affinity
and selectivity was found with a medium size alkylsub-
stituted amido group; iso-butyl (12c). Most probably
there is a limitation as to what size of groups can be
accommodated in this region by TRb, as well as a
dependence on the exact orientation of branching. Bio-
isosteric replacements of the 40-hydroxy position repre-
sent a new thyromimetic class of ligands that will be
further examined in transactivation assay and in rele-
vant animal models.
Supplementary data
Supplementary data associated with this article can be
References and notes
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