Journal of Medicinal Chemistry
Article
(22) Garg, N.; Li, Y. L.; Garcia Collazo, A. M.; Litten, C.; Ryono, D.
E.; Zhang, M.; Caringal, Y.; Brigance, R. P.; Meng, W.; Washburn, W.
N.; Agback, P.; Mellstrom, K.; Rehnmark, S.; Rahimi-Ghadim, M.;
Norin, T.; Grynfarb, M.; Sandberg, J.; Grover, G.; Malm, J. Thyroid
receptor ligands. Part 8: Thyromimetics derived from N-acylated-
alpha-amino acid derivatives displaying modulated pharmacological
selectivity compared with KB-141. Bioorg. Med. Chem. Lett. 2007, 17,
4131−4134.
(23) Shah, V.; Nguyen, P.; Nguyen, N. H.; Togashi, M.; Scanlan, T.
S.; Baxter, J. D.; Webb, P. Complex actions of thyroid hormone
receptor antagonist NH-3 on gene promoters in different cell lines.
Mol. Cell. Endocrinol. 2008, 296, 69−77.
(24) Webb, P.; Nguyen, N. H.; Chiellini, G.; Yoshihara, H. A.; Cunha
Lima, S. T.; Apriletti, J. W.; Ribeiro, R. C.; Marimuthu, A.; West, B. L.;
Goede, P.; Mellstrom, K.; Nilsson, S.; Kushner, P. J.; Fletterick, R. J.;
Scanlan, T. S.; Baxter, J. D. Design of thyroid hormone receptor
antagonists from first principles. J. Steroid Biochem. Mol. Biol. 2002, 83,
59−73.
(25) Nguyen, N. H.; Apriletti, J. W.; Cunha Lima, S. T.; Webb, P.;
Baxter, J. D.; Scanlan, T. S. Rational design and synthesis of a novel
thyroid hormone antagonist that blocks coactivator recruitment. J.
Med. Chem. 2002, 45, 3310−3320.
(26) Arnold, L. A.; Estebanez-Perpina, E.; Togashi, M.; Jouravel, N.;
Shelat, A.; McReynolds, A. C.; Mar, E.; Nguyen, P.; Baxter, J. D.;
Fletterick, R. J.; Webb, P.; Guy, R. K. Discovery of small molecule
inhibitors of the interaction of the thyroid hormone receptor with
transcriptional coregulators. J. Biol. Chem. 2005, 280, 43048−43055.
(27) Arnold, L. A.; Kosinski, A.; Estebanez-Perpina, E.; Fletterick, R.
J.; Guy, R. K. Inhibitors of the interaction of a thyroid hormone
receptor and coactivators: preliminary structure−activity relationships.
J. Med. Chem. 2007, 50, 5269−5280.
(28) Hwang, J. Y.; Arnold, L. A.; Zhu, F.; Kosinski, A.; Mangano, T.
J.; Setola, V.; Roth, B. L.; Guy, R. K. Improvement of pharmacological
properties of irreversible thyroid receptor coactivator binding
inhibitors. J. Med. Chem. 2009, 52, 3892−3901.
(29) Johnson, R. L.; Hwang, J. Y.; Arnold, L. A.; Huang, R.;
Wichterman, J.; Augustinaite, I.; Austin, C. P.; Inglese, J.; Guy, R. K.;
Huang, W. A quantitative high-throughput screen identifies novel
inhibitors of the interaction of thyroid receptor beta with a peptide of
steroid receptor coactivator 2. J. Biomol. Screening 2011, 16, 618−627.
(30) Hwang, J. Y.; Huang, W.; Arnold, L. A.; Huang, R.; Attia, R. R.;
Connelly, M.; Wichterman, J.; Zhu, F.; Augustinaite, I.; Austin, C. P.;
Inglese, J.; Johnson, R. L.; Guy, R. K. Methylsulfonylnitrobenzoates, a
new class of irreversible inhibitors of the interaction of the thyroid
hormone receptor and its obligate coactivators that functionally
antagonizes thyroid hormone. J. Biol. Chem. 2011, 286, 11895−11908.
(31) Warmus, J. S.; Flamme, C.; Zhang, L. Y.; Barrett, S.; Bridges, A.;
Chen, H.; Gowan, R.; Kaufman, M.; Sebolt-Leopold, J.; Leopold, W.;
Merriman, R.; Ohren, J.; Pavlovsky, A.; Przybranowski, S.; Tecle, H.;
Valik, H.; Whitehead, C.; Zhang, E. 2-Alkylamino- and alkoxy-
substituted 2-amino-1,3,4-oxadiazoles-O-alkyl benzohydroxamate es-
ters replacements retain the desired inhibition and selectivity against
MEK (MAP ERK kinase). Bioorg. Med. Chem. Lett. 2008, 18, 6171−
6174.
(32) Diana, G. D.; Volkots, D. L.; Nitz, T. J.; Bailey, T. R.; Long, M.
A.; Vescio, N.; Aldous, S.; Pevear, D. C.; Dutko, F. J. Oxadiazoles as
ester bioisosteric replacements in compounds related to disoxaril.
Antirhinovirus activity. J. Med. Chem. 1994, 37, 2421−2436.
(33) The MOE program (Chemical Computing Group) was used.
(34) Arnold, L. A.; Estebanez-Perpina, E.; Togashi, M.; Shelat, A.;
Ocasio, C. A.; McReynolds, A. C.; Nguyen, P.; Baxter, J. D.; Fletterick,
R. J.; Webb, P.; Guy, R. K. A high-throughput screening method to
identify small molecule inhibitors of thyroid hormone receptor
coactivator binding. Sci. STKE 2006, pl3.
REFERENCES
■
(1) He, J.; Cheng, Q.; Xie, W. Minireview: Nuclear receptor-
controlled steroid hormone synthesis and metabolism. Mol. Endocrinol.
2010, 24, 11−21.
(2) Schulman, I. G. Nuclear receptors as drug targets for metabolic
disease. Adv. Drug Delivery Rev. 2010, 62, 1307−1315.
(3) Sun, G.; Shi, Y. Nuclear receptors in stem cells and their
therapeutic potential. Adv. Drug Delivery Rev. 2010, 62, 1299−1306.
(4) Cheng, S. Y.; Leonard, J. L.; Davis, P. J. Molecular aspects of
thyroid hormone actions. Endocr. Rev. 2010, 31, 139−170.
(5) Kress, E.; Samarut, J.; Plateroti, M. Thyroid hormones and the
control of cell proliferation or cell differentiation: paradox or duality?
Mol. Cell. Endocrinol. 2009, 313, 36−49.
(6) Oppenheimer, J. H.; Schwartz, H. L. Molecular basis of thyroid
hormone-dependent brain development. Endocr. Rev. 1997, 18, 462−
475.
(7) Yaoita, Y.; Brown, D. D. A correlation of thyroid hormone
receptor gene expression with amphibian metamorphosis. Genes Dev.
1990, 4, 1917−1924.
(8) Brent, G. A. Tissue-specific actions of thyroid hormone: insights
from animal models. Rev. Endocr. Metab. Disord. 2000, 1, 27−33.
(9) Harvey, C. B.; Williams, G. R. Mechanism of thyroid hormone
action. Thyroid 2002, 12, 441−446.
(10) Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.;
Schutz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.;
Chambon, P.; Evans, R. M. The nuclear receptor superfamily: the
second decade. Cell 1995, 83, 835−839.
(11) Alonso, M.; Goodwin, C.; Liao, X.; Ortiga-Carvalho, T.;
Machado, D. S.; Wondisford, F. E.; Refetoff, S.; Weiss, R. E. In vivo
interaction of steroid receptor coactivator (SRC)-1 and the activation
function-2 domain of the thyroid hormone receptor (TR) beta in
TRbeta E457A knock-in and SRC-1 knockout mice. Endocrinology
2009, 150, 3927−3934.
(12) Paul, B. D.; Buchholz, D. R.; Fu, L.; Shi, Y. B. SRC-p300
coactivator complex is required for thyroid hormone-induced
amphibian metamorphosis. J. Biol. Chem. 2007, 282, 7472−7481.
(13) Xu, J.; Li, Q. Review of the in vivo functions of the p160 steroid
receptor coactivator family. Mol. Endocrinol. 2003, 17, 1681−1692.
(14) Savkur, R. S.; Burris, T. P. The coactivator LXXLL nuclear
receptor recognition motif. J. Pept. Res. 2004, 63, 207−212.
(15) Darimont, B. D.; Wagner, R. L.; Apriletti, J. W.; Stallcup, M. R.;
Kushner, P. J.; Baxter, J. D.; Fletterick, R. J.; Yamamoto, K. R.
Structure and specificity of nuclear receptor−coactivator interactions.
Genes Dev. 1998, 12, 3343−3356.
(16) Feng, W.; Ribeiro, R. C.; Wagner, R. L.; Nguyen, H.; Apriletti, J.
W.; Fletterick, R. J.; Baxter, J. D.; Kushner, P. J.; West, B. L. Hormone-
dependent coactivator binding to a hydrophobic cleft on nuclear
receptors. Science 1998, 280, 1747−1749.
(17) Yuan, C.; Lin, J. Z.; Sieglaff, D. H.; Ayers, S. D.; Denoto-
Reynolds, F.; Baxter, J. D.; Webb, P. Identical gene regulation patterns
of T3 and selective thyroid hormone receptor modulator GC-1.
Endocrinology 2012, 153, 501−511.
(18) Grover, G. J.; Egan, D. M.; Sleph, P. G.; Beehler, B. C.; Chiellini,
G.; Nguyen, N. H.; Baxter, J. D.; Scanlan, T. S. Effects of the thyroid
hormone receptor agonist GC-1 on metabolic rate and cholesterol in
rats and primates: selective actions relative to 3,5,3′-triiodo-L-
thyronine. Endocrinology 2004, 145, 1656−1661.
(19) Baxter, J. D.; Webb, P.; Grover, G.; Scanlan, T. S. Selective
activation of thyroid hormone signaling pathways by GC-1: a new
approach to controlling cholesterol and body weight. Trends
Endocrinol. Metab. 2004, 15, 154−157.
(20) Messier, N.; Langlois, M. F. Triac regulation of transcription is
T(3) receptor isoform- and response element-specific. Mol. Cell.
Endocrinol. 2000, 165, 57−66.
(21) Bryzgalova, G.; Effendic, S.; Khan, A.; Rehnmark, S.; Barbounis,
P.; Boulet, J.; Dong, G.; Singh, R.; Shapses, S.; Malm, J.; Webb, P.;
Baxter, J. D.; Grover, G. J. Anti-obesity, anti-diabetic, and lipid
lowering effects of the thyroid receptor beta subtype selective agonist
KB-141. J. Steroid Biochem. Mol. Biol. 2008, 111, 262−267.
(35) Sadana, P.; Hwang, J. Y.; Attia, R. R.; Arnold, L. A.; Neale, G.;
Guy, R. K. Similarities and differences between two modes of
antagonism of the thyroid hormone receptor. ACS Chem. Biol. 2011, 6,
1096−1106.
2309
dx.doi.org/10.1021/jm201546m | J. Med. Chem. 2012, 55, 2301−2310