IP Library › Granted Patent US 12,466,781
Granted Patent B2
US 12,466,781 · App. 17/780,465 · Granted Nov 11, 2025

Thyromimetics

Inventors: Thomas von Geldern (Richmond, IL); Bradley Backes (San Francisco, CA); Baoku He (Jiangsu, CN); Jason Harris (San Diego, CA)
Assignee: AUTOBAHN THERAPEUTICS, INC.
C07C69/734A61P11/00C07C59/70C07C235/74C07C243/18C07C259/06C07D205/04C07D261/14
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Quick Facts
Patent No.
US 12,466,781
App. No.
17/780,465
Granted
Nov 11, 2025
Kind
B2
Abstract

Compounds are provided having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1 , R 2 , X 1 , X 2 , Y 1 , and Y 2 are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Claims (35)

1 . A compound having the structure of Formula (I):

or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein:

X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo;

X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo;

Y 1 and Y 2 are each, independently, H, cyano, halogen, lower alkyl, or lower alkoxy, wherein at least one of Y 1 and Y 2 is not H;

R 1 is —NR 1a R 1b or —OR 1c ;

R 1a and R 1b are each, independently, H, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form heterocycle;

R 1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl; and

R 2 is lower alkyl, lower alkenyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

wherein R 1a , R 1b , R 1c , and R 2 are each, independently, optionally substituted with one or more halo, lower alkyl, lower haloalkyl, cyano, —OR′, —NR′R″, ═O, ═S, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein R 2 is lower alky 1 optionally substituted with one or more halo, cyano, —OR′, —NR′R″, ═O, ═S, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.

3 . The compound of claim 2 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein R 2 is unsubstituted lower alkyl.

4 . The compound of claim 3 having the structure of Formula (II-A):

or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein:

X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo;

X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo;

Y 1 and Y 2 are each, independently, H, cyano, halogen, lower alkyl, or lower alkoxy, wherein at least one of Y 1 and Y 2 is not H; and

R 1a and R 1b are each, independently, H, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form heterocycle;

wherein R 1a and R 1b are each, independently, optionally substituted with one or more halo, cyano, —OR′, —NR′R″, ═O, ═S, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.

5 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein R 1a is lower alkyl and R 1b is H.

6 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower alkyl.

7 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein X 1 is halo.

8 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower alkyl.

9 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein X 2 is halo.

10 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein X 1 is Cl and X 2 is Cl.

11 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 1 is halogen.

12 . The compound of claim 11 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 1 is F.

13 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H.

14 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 2 is halogen.

15 . The compound of claim 14 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 2 is F.

16 . The compound of claim 4 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, wherein Y 2 is H.

17 . The compound of claim 1 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, having the structure of any one of the following compounds:

18 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient.

19 . A method of treating a subject having a neurodegenerative disease comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20 . The method of claim 19 , wherein the neurodegenerative disease is adult Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis, cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, diffuse myelinoclastic sclerosis, idiopathic inflammatory demyelinating disease, infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignarni disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knaap disease, X-linked adrenoleukodystrophy, or Zellweger syndrome.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 19, 2022
From: GELDERN, THOMAS VON; BACKES, BRADLEY; HE, BAOKU; HARRIS, JASON
To: AUTOBAHN THERAPEUTICS, INC.
Reel/Frame 061263/0896 →
Priority Claims (2)
WO PCT/CN2019/122062 · Nov 29, 2019 · international
WO PCT/CN2020/085540 · May 1, 2020 · international
Continuity (1)
Related Publication 20230048992A1 · Feb 16, 2023
References Cited (208)
US 3845770A · Theeuwes et al. · 1974 [cited by applicant]
US 4326525A · Swanson et al. · 1982 [cited by applicant]
US 4652441A · Okada et al. · 1987 [cited by applicant]
US 4675189A · Kent et al. · 1987 [cited by applicant]
US 4677191A · Tanaka et al. · 1987 [cited by applicant]
US 4723027A · Stoutamire et al. · 1988 [cited by applicant]
US 4728721A · Yamamoto et al. · 1988 [cited by applicant]
US 4741897A · Andrews et al. · 1988 [cited by applicant]
US 4917893A · Okada et al. · 1990 [cited by applicant]
US 4992445A · Lawter et al. · 1991 [cited by applicant]
US 5001139A · Lawter et al. · 1991 [cited by applicant]
US 5023252A · Hseih · 1991 [cited by applicant]
US 5466569A · Eber et al. · 1995 [cited by applicant]
US 5616345A · Geoghegan et al. · 1997 [cited by applicant]
US 5883294A · Scanlan et al. · 1999 [cited by applicant]
US 6054485A · Schwartz et al. · 2000 [cited by applicant]
US 6107517A · Scanlan et al. · 2000 [cited by applicant]
US 6236946B1 · Scanlan et al. · 2001 [cited by applicant]
US 7288571B2 · Hangeland et al. · 2007 [cited by applicant]
US 7302347B2 · Baxter et al. · 2007 [cited by applicant]
US 7915261B2 · Ishii et al. · 2011 [cited by applicant]
US 7919494B2 · Ishii et al. · 2011 [cited by applicant]
US 7919495B2 · Ishii et al. · 2011 [cited by applicant]
US 9562012B2 · Tanis et al. · 2017 [cited by applicant]
US 9701650B2 · Scanlan et al. · 2017 [cited by applicant]
US 10130643B2 · Cable et al. · 2018 [cited by applicant]
US 10226438B2 · Scanlan et al. · 2019 [cited by applicant]
US 10392356B2 · Scanlan et al. · 2019 [cited by applicant]
US 10544075B2 · Scanlan et al. · 2020 [cited by applicant]
US 10870616B2 · Scanlan et al. · 2020 [cited by applicant]
US 11104654B2 · Scanlan et al. · 2021 [cited by applicant]
US 11325886B2 · Scanlan et al. · 2022 [cited by applicant]
US 11510887B2 · Scanlan et al. · 2022 [cited by applicant]
US 11578032B2 · Scanlan · 2023 [cited by applicant]
US 11613517B2 · Scanlan et al. · 2023 [cited by applicant]
US 20030203898A1 · Haning et al. · 2003 [cited by applicant]
US 20030215434A1 · Khan et al. · 2003 [cited by applicant]
US 20050282872A1 · Hangeland et al. · 2005 [cited by applicant]
US 20070021407A1 · Boyle et al. · 2007 [cited by applicant]
US 20080124280A1 · Mousa et al. · 2008 [cited by applicant]
US 20080221170A1 · Roberts et al. · 2008 [cited by applicant]
US 20090028925A1 · Erion et al. · 2009 [cited by applicant]
US 20090062330A1 · Kalafer et al. · 2009 [cited by applicant]
US 20090105347A1 · Scanlan et al. · 2009 [cited by applicant]
US 20090232879A1 · Cable et al. · 2009 [cited by applicant]
US 20090306225A1 · Lichter et al. · 2009 [cited by applicant]
US 20090318514A1 · Garcia Collazo et al. · 2009 [cited by applicant]
US 20100099608A1 · Browning · 2010 [cited by applicant]
US 20100216771A1 · Li · 2010 [cited by applicant]
US 20100303934A1 · Soumyanath et al. · 2010 [cited by applicant]
US 20110178134A1 · Jaehne et al. · 2011 [cited by applicant]
US 20120004166A1 · Keil et al. · 2012 [cited by applicant]
US 20120245213A1 · Mosinger et al. · 2012 [cited by applicant]
US 20130289024A1 · Johansen et al. · 2013 [cited by applicant]
US 20140235676A1 · Landreth · 2014 [cited by applicant]
US 20140288077A1 · Fujii et al. · 2014 [cited by applicant]
US 20160081955A1 · Scanlan et al. · 2016 [cited by applicant]
US 20160244418A1 · Scanlan et al. · 2016 [cited by applicant]
US 20170007589A1 · Ding et al. · 2017 [cited by applicant]
US 20170226154A1 · Evans et al. · 2017 [cited by applicant]
US 20180057472A1 · Scanlan et al. · 2018 [cited by applicant]
US 20190175531A1 · Scanlan et al. · 2019 [cited by applicant]
US 20200181103A1 · Scanlan et al. · 2020 [cited by applicant]
US 20200361849A1 · Von Geldern et al. · 2020 [cited by applicant]
US 20200405669A1 · Scanlan et al. · 2020 [cited by applicant]
US 20210002208A1 · Scanlan · 2021 [cited by applicant]
US 20210053917A1 · Von Geldern et al. · 2021 [cited by applicant]
US 20210087137A1 · Scanlan et al. · 2021 [cited by applicant]
CN 1882327A · 2006 [cited by applicant]
CN 101180097A · 2008 [cited by applicant]
CN 101189248A · 2008 [cited by applicant]
CN 101547898A · 2009 [cited by applicant]
CN 101600450A · 2009 [cited by applicant]
CN 101610774A · 2009 [cited by applicant]
CN 101848712A · 2010 [cited by applicant]
CN 107848940A · 2018 [cited by applicant]
EP 3259246A1 · 2017 [cited by applicant]
JP S59116256A · 1984 [cited by applicant]
JP H09301917A · 1997 [cited by applicant]
JP 2004512303A · 2004 [cited by applicant]
JP 2004517037A · 2004 [cited by applicant]
JP 2008542301A · 2008 [cited by applicant]
JP 2008545711A · 2008 [cited by applicant]
JP 2012106996A · 2012 [cited by applicant]
JP 2016517884A · 2016 [cited by applicant]
PE 20180021A1 · 2018 [cited by applicant]
RU 2007148927A · 2009 [cited by applicant]
WO WO9321146A1 · 1993 [cited by applicant]
WO WO9900353A1 · 1999 [cited by applicant]
WO WO0039077A2 · 2000 [cited by applicant]
WO WO0073292A1 · 2000 [cited by applicant]
WO WO0160784A1 · 2001 [cited by applicant]
WO WO0190053A1 · 2001 [cited by applicant]
WO WO0200167A2 · 2002 [cited by applicant]
WO WO0234260A1 · 2002 [cited by applicant]
WO WO02072539A1 · 2002 [cited by applicant]
WO WO02081426A1 · 2002 [cited by applicant]
WO WO2004043939A1 · 2004 [cited by applicant]
WO WO2006031922A2 · 2006 [cited by applicant]
WO WO2006128056A2 · 2006 [cited by applicant]
WO WO2006128058A2 · 2006 [cited by applicant]
WO WO2007110226A1 · 2007 [cited by applicant]
WO WO2008125724A1 · 2008 [cited by applicant]
WO WO2013006734A1 · 2013 [cited by applicant]
WO WO2014078892A1 · 2014 [cited by applicant]
WO WO2014178892A1 · 2014 [cited by applicant]
WO WO2014178931A1 · 2014 [cited by applicant]
WO WO2015188015A1 · 2015 [cited by applicant]
WO WO2016134292A1 · 2016 [cited by applicant]
WO WO2017015360A1 · 2017 [cited by applicant]
WO WO2017201320A1 · 2017 [cited by applicant]
WO WO2018032012A1 · 2018 [cited by applicant]
WO WO2018208707A1 · 2018 [cited by applicant]
WO WO2019160980A1 · 2019 [cited by applicant]
WO WO2020118564A1 · 2020 [cited by applicant]
WO WO2020123861A1 · 2020 [cited by applicant]
WO WO2020180624A1 · 2020 [cited by applicant]
WO WO2021108549A1 · 2021 [cited by applicant]
Actis et al., Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis. Bioorg Med Chem. 21(7):1972-1977 (2013). [cited by applicant]
Alonso-Merino et al., Thyroid hormones inhibit TGF-beta signaling and attenuate fibrotic responses. Proc Natl Acad Sci U S A. 113(24):E3451-E3460 (2016). [cited by applicant]
Ashraf et al., Synthesis, characterization and in vitro hydrolysis studies of ester and amide prodrugs of dexibuprofen. Medicinal Chemistry Research 21:3361-3368 (2012). [cited by applicant]
Balkwill et al., Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211-217 (2005). [cited by applicant]
Bastin et al. Salt selection and optimisation procedures for pharmaceutical new chemical entities. Organic Process Research & Development 4.5:427-435 (2000). [cited by applicant]
Baxi et al., A selective thyroid hormone beta receptor agonist enhances human and rodent oligodendrocyte differentiation. Glia 62(9):1513-1529 (2014). [cited by applicant]
Baxter et al., Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight. Trends Endocrinol Metab. 15(4):154-157 (2004). [cited by applicant]
Baxter et al., Selective modulation of thyroid hormone receptor action. J. Steroid Biochem. Mol. Bio. 76:31-42 (2001). [cited by applicant]
Belikov. Pharmaceutical Chemistry: Manual. Moscow: MEDpress-inform (pp. 27-29) (2007). [cited by applicant]
Berge et al. Pharmaceutical Salts. Journal of Pharmaceutical Sciences 66(1):1-19 (Jan. 1977). [cited by applicant]
Berkenstam et al., The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A 105(2):663-667 (2008). [cited by applicant]
Bernal et al., Action of thyroid hormone in brain. J Endocrinol Invest. 25(3):268-288 (2002). [cited by applicant]
Bernal et al., Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab. 3(3):249-259 (2007). [cited by applicant]
Biondi et al., Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24: 1-13 (2004). [cited by applicant]
Boger et al., Fatty acid amide hydrolase substrate specificity. Bioorg Med Chem Lett. 10(23):2613-2616 (2000). [cited by applicant]
Borngraeber et al. Ligand Selectivity by Seeking Hydrophobicity in Thyroid Hormone Receptor. PNAS USA 100(26):15358-15363 (2003). [cited by applicant]
Boymond et al., Preparation of highly functionalized grignard reagents by an iodine-magnesium exchange reaction and its application in solid-phase synthesis. Angew Chem Int Ed Engl. 37(12):1701-1703 (1998). [cited by applicant]
Calza et al., Thyroid hormone and remyelination in adult central nervous system: a lesson from an inflammatory-demyelinating disease. Brain Res Brain Res Rev. 48(2):339-346 (2005). [cited by applicant]
Chiellini et al., A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chemistry and Biology 5(6):299-306 (1998). [cited by applicant]
Chiellini et al., Synthesis and biological activity of novel thyroid hormone analogues: 5′-aryl substituted GC-1 derivatives. Bioorg Med Chem. 10(2):333-346 (2002). [cited by applicant]
Cravatt et al., Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 98(16):9371-9376 (2001). [cited by applicant]
Dell'Acqua et al., Functional and molecular evidence of myelin- and neuroprotection by thyroid hormone administration in experimental allergic encephalomyelitis. Neuropathol Appl Neurobiol. 38(5):454-470 (2012). [cited by applicant]
Devereaux et al., Increasing thyromimetic potency through halogen substitution. ChemMedChem. 11(21):2459-2465 (2016). [cited by applicant]
D'Intino et al., Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism. J Neuroendocrinol. 23(9):778-790… [cited by applicant]
Doran et al., The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos. 33(1):165-174 (2005). [cited by applicant]
Edgar et al., An efficient and selective method for the preparation of iodophenols. Journal of Organic Chemistry 55:5287-5291 (1990). [cited by applicant]
Engelen et al., X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 7:51 [1-14] (2012). [cited by applicant]
Erion et al., Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A 104(39):15490-15495 (2007). [cited by applicant]
Ferrara et al., Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem. 25(10):2743-2753 (2017). [cited by applicant]
Fourcade et al., Thyroid hormone induction of the adrenoleukodystrophy-related gene (ABCD2). Mol. Pharmacol. 63:1296-1303 (2003). [cited by applicant]
Genin et al., Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics. J Steroid Biochem Mol Biol. 116(1-2):37-43 (2009). [cited by applicant]
Gold et al. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953-1971 (2006). [cited by applicant]
Gould et al. Salt Selection for Basic Drugs. Int J. Pharm. 33:201-217 (1986). [cited by applicant]
Grover et al., 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 145(4):1656-1661 (2004). [cited by applicant]
Hafer-Macko et al., Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann. Neurol. 39:625-635 (1996). [cited by applicant]
Hangeland et al., Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta. Bioorg Med Chem Lett 14(13):3549-3553 (2004). [cited by applicant]
Hartley et al., A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy. Endocrinology 158(5):1328-1338 (2017). [cited by applicant]
Johnson, Demyelinating diseases, in: The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Institute of Medicine (US) Forum on Micr… [cited by applicant]
Kavirajan et al., Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol. 6(9):782-792 (2007). [cited by applicant]
Koenning et al., Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci. 32(36):12528-12542 (2012). [cited by applicant]
Krogsgaard-Larsen et al. Chapter 4: Design and application of prodrugs. Textbook of Drug Designing and Discovery, US, Taylor & Francis Inc (3rd Ed.) (pp. P460-P514). [cited by applicant]
Lee et al., Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacological Review 53(4):569-596 (2001). [cited by applicant]
Link et al., Photo-caged agonists of the nuclear receptors RARgamma and TRbeta provide unique time-dependent gene expression profiles for light-activated gene patterning. Bioorg Med Chem. 12(22):5949-5959 (2004). [cited by applicant]
Lu et al., An expedient synthesis of benzyl 2,3,4-tri-O-benzyl-beta-D-glucopyranoside and benzyl 2,3,4-tri-O-benzyl-beta-D-mannopyranoside. Carbohydr Res. 340(6):1213-1217 (2005). [cited by applicant]
Malm et al., Recent advances in the development of agonists selective for beta1-type thyroid hormone receptor. Mini Rev Med Chem. 7(1):79-86 (2007). [cited by applicant]
Mandal et al., Pd-C-induced catalytic transfer hydrogenation with triethylsilane. Journal of Organic Chemistry 72(17):6599-6601 (2007). [cited by applicant]
Martin et al. The proliferating cell nuclear antigen regulates retinoic acid receptor transcriptional activity through direct protein-protein interaction. Nucleic Acids Res. 33(13):4311-21 (2005). [cited by applicant]
Massague. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 13(10):616-630 (2012). [cited by applicant]
Meinig et al., Structure-activity relationships of central nervous system penetration by fatty acid amide hydrolase (FAAH)-targeted thyromimetic prodrugs. ACS Med Chem Lett. 10(1):111-116 (2018). [cited by applicant]
Meinig et al., Targeting fatty-acid amide hydrolase with prodrugs for CNS-selective therapy. ACS Chem Neurosci. 8(11):2468-2476 (2017). [cited by applicant]
Miller et al., Primary-progressive multiple sclerosis. Lance Neurol. 6:903-912 (2007). [cited by applicant]
Miyabara et al., Thyroid hormone receptor-beta-selective agonist GC-24 spares skeletal muscle type I to II fiber shift. Cell Tissue Res. 321(2):233-241 (2005). [cited by applicant]
Montalban et al. Primary progressive multiple sclerosis diagnostic criteria: a reappraisal. Mult Scler 15(12):1459-65 (2009). [cited by applicant]
Nguyen et al., Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists. J Am Chem Soc. 127(13):4599-4608 (2005). [cited by applicant]
Nguyen et al., Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. J Med Chem. 45(15):3310-3320 (2002). [cited by applicant]
Ocasio et al., Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents. Bioorg Med Chem. 16(2):762-770 (2008). [cited by applicant]
Ocasio et al., Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist. ACS Chem Biol. 1(9):585-593 (2006). [cited by applicant]
O'Shea et al., Characterization of skeletal phenotypes of TRalpha1 and TRbeta mutant mice: implications for tissue thyroid status and T3 target gene expression. Nucl Recept Signal 4:e011 [1-5] (2006). [cited by applicant]
Oppenheimer et al., Molecular basis of thyroid hormone-dependent brain development. Endocrine Reviews 18(4):462-475 (1997). [cited by applicant]
Patani et al. Bioisosterism: A Rational Approach in Drug Design. Chem. Rev. 96:3147-3176 (1996). [cited by applicant]
PCT/US2020/062229 International Invitation to Pay Additional Fees dated Jan. 27, 2021. [cited by applicant]
PCT/US2020/062229 International Search Report and Written Opinion dated Mar. 24, 2021. [cited by applicant]
Penning et al., Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. Journal of Medicinal Chemistry 43(4):721-735 (200… [cited by applicant]
Placzek et al., New synthetic routes to thyroid hormone analogs: d(6)-sobetirome, (3)H-sobetirome, and the antagonist NH-3. Tetrahedron 71(35):5946-5951 (2015). [cited by applicant]
Placzek et al., Sobetirome prodrug esters with enhanced blood-brain barrier permeability. Bioorg Med Chem. 24(22):5842-5854 (2016). [cited by applicant]
PubChem SID 235918886 [https://pubchem.ncbi.nlm.nih.gov/substance/235918886] (2015). [cited by applicant]
PubChem SID 319635332 [https://pubchem.ncbi.nlm.nih.gov/substance/319635332] (2016). [cited by applicant]
Reichel et al., The role of blood-brain barrier studies in the pharmaceutical industry. Curr Drug Metab. 7(2):183-203 (2006). [cited by applicant]
Scanlan. Safety and Pharmacodynamic Study of Sobetirome in X-Linked Adrenoleukodystrophy (X-ALD), available online at ClinicalTrials.gov on Feb. 6, 2013, 3 pages (clinicaltrials.gov/ct2/show/NCT01787578?term=Scanlan&ran… [cited by applicant]
Scanlan. Sobetirome: a case history of bench-to-clinic drug discovery and development. Heart Fail Rev 15:177-182 (2010). [cited by applicant]
Shiohara et al., Discovery of novel indane derivatives as liver-selective thyroid hormone receptor beta (TRbeta) agonists for the treatment of dyslipidemia. Bioorg Med Chem 20(11):3622-3634 (2012). [cited by applicant]
Smith et al., Water soluble prodrug of a COX-2 selective inhibitor suitable for intravenous administration in models of cerebral ischemia. Bioorganic & Medicinal Chemistry Letters 15(13):3197-3200 (2005). [cited by applicant]
Takahashi et al., Characterisation of liver-specific distribution of a novel 1-benzyl-4-aminoindole-based thyroid hormone receptor beta agonist, SKL-13784: comparison with GC-1. Xenobiotica 46(2):108-116 [1-9] (2016; pu… [cited by applicant]
Takahashi et al., In vivo evaluation of 1-benzyl-4-aminoindole-based thyroid hormone receptor beta agonists: importance of liver selectivity in drug discovery. Biol Pharm Bull. 37(7):1103-1108 (2014). [cited by applicant]
Takahashi et al., Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor beta agonists. Bioorg Med Chem. 22(1):488-498 (2014). [cited by applicant]
Tancevski et al., The resurgence of thyromimetics as lipid-modifying agents. Curr Opin Investig Drugs 10(9):912-918 (2009). [cited by applicant]
Tangdenpaisal et al., Synthesis of the thyroid hormone analog GC-1 via Bi(OTf)3-catalyzed benzylation. Tetrahedron 70: 6789-6795 (2014). [cited by applicant]
Taub et al., Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis 230(2):373-380 (2013). [cited by applicant]
Tegeli et al. Synthesis and evaluation of amide prodrugs of mefenamic acid. International Journal of Chemical Sciences 12(3):1033-1043. [cited by applicant]
Thyroid. Abstract from poster presented at the 87th Annual Meeting of the American Thyroid Association (Oct. 18-22, 2017). [cited by applicant]
Trost et al., The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141(9):3057-3064 (2000). [cited by applicant]
U.S. Department of Health and Human Services, Health Resources and Services Administration (HRSA), Orphan Drug Designations and Approvals List as of Sep. 3, 2013. http://www.hrsa.gov/opa/programrequirements/orphandrugse… [cited by applicant]
Valadares et al. Role of halogen bonds in thyroid hormone receptor selectivity: pharmacophore-based 3D-QSSR studies. J Chem Inf Model 49(11):2606-2616 (2009). [cited by applicant]
Varga et al., Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr Opin Rheumatol. 20(6):720-728 (2008). [cited by applicant]
Vattakatuchery et al., Acetylcholinesterase inhibitors in cognitive impairment in Huntington's disease: A brief review. 3(3):62-64 (2013). [cited by applicant]
Ye et al, Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. J Med Chem. 46(9):1580-1588 (2003). [cited by applicant]
Yen., Physiological and molecular basis of thyroid hormone action. Physiological Reviews 81(3):1097-1142 (2001). [cited by applicant]
Yoshihara et al., A designed antagonist of the thyroid hormone receptor. Bioorg Med Chem Lett. 11(21):2821-2825 (2001). [cited by applicant]
Yoshihara et al., Structural determinants of selective thyromimetics. J Med Chem. 46(14):3152-3161 (2003). [cited by applicant]
Zhang et al., Thyroid hormone potentially benefits multiple sclerosis via facilitating remyelination. Mol Neurobiol. 53(7):4406-4416 (2016). [cited by applicant]
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