Tiratricol

 

Tiratricol

CAS 51-24-1, 1477-04-9 (hydrochloride salt)

MFC₁₄H₉I₃O₄ MW621.93 g/mol

9/28/2026, Emcitate, FDA 2026, APPROVALS 2026, Triac

2-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid

• 3,3',5-TRIIODOTHYROACETIC ACID
• Triiodothyroacetic acid

To treat peripheral thyrotoxicosis in patients with MCT8 deficiency

Tiratricol is a monocarboxylic acid that is (4-hydroxy-3,5-diiodophenyl)acetic acid in which the phenolic hydroxy group has been replaced by a 4-hydroxy-3-iodophenoxy group. It is a thyroid hormone analogue that has been used in the treatment of thyroid hormone resistance syndrome. It has a role as an antiviral agent, a nutraceutical, a thyroid hormone, an anti-obesity agent, an EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor and a human metabolite. It is a monocarboxylic acid, a member of phenols, an aromatic ether and an organoiodine compound

Tiratricol (also known as TRIAC or triiodothyroacetic acid), sold under the brand name Emcitate, is a thyroid hormone analogue. Triiodothyroacetic acid is also a physiologic thyroid hormone that is present in the normal organism in low concentrations. Tiratricol is an analogue of a naturally circulating metabolite of the active thyroid hormone T3.^[1] MCT8 is a specific thyroid hormone transporter.^[1] While T3 and T4 thyroid hormones rely on MCT8 to enter several tissues such as the brain, tiratricol can enter cells independently of MCT8.^[1] Once inside cells, tiratricol activates the thyroid hormone receptor in a similar way to endogenous T3.^[1]

The most common side effects are excessive sweating, irritability, anxiety and nightmares.^[1]

Medical uses

Tiratricol is indicated in the management of thyroid hormone resistance syndrome.^[3]

In the United States, Tiratricol is indicated for the treatment of peripheral thyrotoxicosis in adults and pediatric patients with MCT8 deficiency (Allan–Herndon–Dudley syndrome).^[4][5]

Society and culture

Legal status

Tiratricol is not approved for sale in Canada. It was once an approved medication in Brazil, but its marketing authorization was suspended in 2003, effectively prohibiting its sale.^[6] Tiratricol is available in France for therapy of thyroid hormone resistance and adjuvant therapy of thyroid cancer.^[7]

In December 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Emcitate, intended for the treatment of MCT8 deficiency (Allan-Herndon-Dudley syndrome).^[1][8] The applicant for this medicinal product is Rare Thyroid Therapeutics International AB.^[1] Emcitate is a hybrid medicine of Téatrois, which has been authorized in France.^[1] Emcitate contains the same active substance as Téatrois but has a different indication.^[1] Tiratricol was authorized for medical use in the European Union in February 2025.^[1][2] Tiratricol was approved for medical use in the United States kn September 2026.^[5]

Research

Tiratricol has been investigated for use in reducing goiter.^[9]

It has also shown some effectiveness in reducing the atrophy caused when using corticosteroids.^[10]

Tiratricol has also been widely marketed, under various trade names, as a weight loss aid. In 1999 and 2000, the United States Food and Drug Administration and Health Canada both issued warnings to the public regarding the use of dietary supplements containing tiratricol.^[11][12]

LIT

C. E. Wilkinson (Biochem. J. 63, 601, 1956): The primary landmark study describing the controlled iodination approach to yield triiodothyroacetic acid.

Meltzer et al. (J. Org. Chem. 26, 1418, 1961): Advanced methods for the synthesis and purification of thyroacetic acid derivatives.

PAT

British Patent GB 803149 (1958)

https://patentscope.wipo.int/search/en/detail.jsf?docId=GB134699786&_cid=P10-MUQCJP-66503-1

EXAMPLE 1 3:5:31 - triiodo - 4 - (41 - hydroxyphenoxy)
phenyl acetic acid (Triac)
An aqueous solution of iodine (N: 40 mls.) was added dropwise with stirring during hour to a solution of 3:5-diiodo-4-(41hydroxyphenoxy)phenyl acetic acid (Diac) (9.92 g.; 0.02 mol.) in aqueous ethylamine (33%: 120 mls.). After a further hour the solution was acidified with hydrochloric acid (5N) at 10-15 (ice-bath cooling). The precipitate, which became gummy on filtration, was triturated with water containing a few drops of hydrochloric acid and again filtered.

The solid was then ground with water containing a little hydrochloric acid, filtered, washed with water and dried over phosphorus pentoxide (12.10 g.; m.p. 161-72 ). The crude product was dissolved in methanol (240 mls.) and stirred during the dropwise addition of water (180 mls.). After standing overnight, the mixture was decanted from the tarry material which had separated. Water (60 mls.) was added in one portion, and the milky solution allowed to stand several hours until crystallisation was complete. The product was collected and dried over phosphorus pentoxide, 7.1 g. (63%) m.p. 181-3 (after sinteringg at about 60 , effervescing at 100 and resolidifying at about 115 ). A sample from a previous experiment was dried by heating slowly to 100 in high vacuum over phosphorus pentoxide. Found: C, 27.3; H, 1.5; I, 61.2, C14H9O4I3 requires C, 27.0; H, 1.5; I, 61.2%.

To prepare the sodium salt of Triac 42.8 g. of Triac was dissolved in a hot solution of sodium carbonate (7.3 g.) in water (420 mis.) and filtered. A solution of salt (35%; 42 mis.) was added and the mixture cooled, finally in the refrigerator. The product was collected and dried to constant weight over phosphorus pentoxide (34.1 g.).

PAT

British Patent GB 805761 (1958)

PAT

US Patent US8071134B2

https://patentscope.wipo.int/search/en/detail.jsf?docId=US42563548&_cid=P10-MUQCHB-64862-1

PAT

Chinese Patent CN113181152B

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN333439736&_cid=P10-MUQCEZ-62879-1

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References

1. "Emcitate EPAR". European Medicines Agency (EMA). 12 December 2024. Retrieved 16 December 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
2. "Emcitate PI". Union Register of medicinal products. 17 February 2025. Retrieved 27 February 2025.
3. Carvalho GA, Ramos HE (2004). "[Thyroid hormone resistance syndrome]" (PDF). Arq Bras Endocrinol Metabol (in Portuguese). 48 (1): 83–92. doi:10.1590/S0004-27302004000100010. PMID 15611821.
4. "EMCITATE — Now Approved". EMCITATE® — Now Approved. Retrieved 29 September 2026.
5. "Egetis Therapeutics Announces U.S. FDA Approval of EMCITATE® (tiratricol) for Patients with MCT8 Deficiency". Egetis Therapeutics. Retrieved 29 September 2026.
6. "Anvisa suspende Tiratricol" (in Portuguese). Brazilian Society of Endocrinology and Metabolism. Archived from the original on 9 October 2007. Retrieved 8 August 2007.
7. Laboratoires DB PHARMA: Teatrois Deprecated link archived 2015-01-19 at archive.today information
8. "First treatment for peripheral thyrotoxicosis in patients with Allan-Herndon-Dudley syndrome". European Medicines Agency (EMA) (Press release). 13 December 2024. Retrieved 16 December 2024.
9. Brenta G, Schnitman M, Fretes O, et al. (November 2003). "Comparative efficacy and side effects of the treatment of euthyroid goiter with levo-thyroxine or triiodothyroacetic acid". J. Clin. Endocrinol. Metab. 88 (11): 5287–92. doi:10.1210/jc.2003-030095. PMID 14602763.
10. Yazdanparast P, Carlsson B, Oikarinen A, Risteli J, Lavin T, Faergemann J (November 2006). "Action of topical thyroid hormone analogue, triiodothyroacetic acid in reversing glucocorticoid-induced skin atrophy in humans". Thyroid. 16 (11): 1157–62. doi:10.1089/thy.2006.16.1157. PMID 17123343.
11. "FDA Warns Against Consuming Dietary Supplements Containing Tiratricol" (Press release). U.S. Food and Drug Administration. 21 November 2000. Archived from the original on 22 January 2001. Retrieved 8 August 2007.
12. "Health Canada issues warning on products containing Tiratricol (TRIAC)" (Press release). Health Canada. 2 December 1999. Retrieved 8 August 2007.

Clinical data
Trade names	Emcitate
Other names	3,3',5-triiodothyroacetic acid TRIAC
AHFS/Drugs.com	International Drug Names
Drug class	Thyroid hormone
ATC code	H03AA04 (WHO) D11AX08 (WHO)
Legal status
Legal status	EU: Rx-only[1][2]
Pharmacokinetic data
Metabolism	Liver glucuronidation
Excretion	Bile duct
Identifiers
IUPAC name
CAS Number	51-24-1
PubChem CID	5803
IUPHAR/BPS	2637
DrugBank	DB03604
ChemSpider	5598
UNII	29OQ9EU4R1
KEGG	D07214
ChEBI	CHEBI:40021
ChEMBL	ChEMBL41632
CompTox Dashboard (EPA)	DTXSID2045232
ECHA InfoCard	100.000.079
Chemical and physical data
Formula	C14H9I3O4
Molar mass	621.935 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

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Zilurgisertib

 

Zilurgisertib

CAS 2173389-57-4

MW 502.6 g/mol MFC₃₀H₃₈N₄O₃

Atebrioz, FDA 2026, APPROVALS 2026, L5Z9S25HO2, INCB 000928

2-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-5-[4-[(1R,5S)-3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]phenyl]pyridine-3-carboxamide

To reduce the volume of total new heterotopic ossification in adults and pediatric patients 12 years and older with fibrodysplasia ossificans progressiva

Zilurgisertib is an inhibitor of activin A receptor type 1 (activin receptor-like kinase 2; ALK2; ALK-2; ACVR1; ACTR-I), with potential anti-anemic and ossification suppressive activities. Upon administration, zilurgisertib targets, binds to and inhibits the activity of ALK-2. This prevents ALK2-mediated signaling and ALK2-mediated excessive bone morphogenetic protein (BMP) signaling. This may suppress heterotopic ossification (HO). As ALK-2 enhances the secretion of hepcidin, a peptide liver hormone and a key modulator of iron homeostasis, zilurgisertib is able to decrease hepcidin expression in the liver, thereby increasing and restoring plasma iron levels, enhancing erythropoiesis, and correcting anemia of chronic disease (ACD). ALK2, a serine/threonine receptor kinase and type I cell surface receptor for BMPs, is constitutively activated due to activating mutations in inflammatory conditions, various types of cancer, and in fibrodysplasia ossificans progressiva (FOP). Elevated serum hepcidin levels enhance storage of iron, reduce iron availability and causes iron deficiency anemia.

Zilurgisertib, sold under the brand name Atebrioz, is a medication used for the treatment of fibrodysplasia ossificans progressiva.^[1] It is an selective activin receptor-like kinase-2 (ALK2) inhibitor.^[1][2]

Zilurgisertib was approved for medical use in the United States in September of 2026.^[3]

Medical uses

Zilurgisertib is indicated to reduce the volume of total new heterotopic ossification (abrnomal bone formation) in people aged twelve years of age and older with fibrodysplasia ossificans progressiva.^[1]

Fibrodysplasia ossificans progressiva is a rare genetic disease caused certain mutations in the ACVR1/ALK2 gene which controls new bone growth.^[3] As a result, connective tissues such as muscle, tendons, and ligaments gradually turn into bone, causing limited movement, deformities, severe disability, and early death.^[3]

Adverse effects

Zilurgisertib can cause fetal harm based on data from animal studies.^[3]

The most common side effects include headache, joint pain, upper respiratory tract infection, nosebleeds, and nausea.^[3]

History

The effectiveness of zilurgisertib was evaluated in a randomized, double-blind, placebo‑controlled trial (NCT05090891) in which 63 participants with FOP were randomly assigned to receive zilurgisertib 100 mg or placebo once daily for 24 weeks followed by a 292-week, single-arm, open-label extension period during which participants received oral zilurgisertib 100 mg daily.^[3]

Society and culture

Legal status

Zilurgisertib was approved for medical use in the United States in September 2026.^[4] The US Food and Drug Administration granted the application for zilurgisertib fast track, priority review, and orphan drug designations for this indication.^[3]

Names

Zilurgisertib is the international nonproprietary name.^[5]

Zilurgisertib is sold under the brand name Atebrioz.^[3]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US242623881&_cid=P22-MUNHEN-48106-1

Example 34: 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (also named compound A herein)

To a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid TFA salt (Intermediate 14a, 4.10 g, 8.14 mmol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (2.17 g, 12.2 mmol) in anhydrous DMF (60 mL) was added N-methylmorpholine (2.24 mL, 20.4 mmol) and HATU (4.64 g, 12.2 mmol) under a nitrogen atmosphere at RT. The reaction mixture was stirred for 2 h and then diluted with a sat. aq. solution of NaHCO 3 and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (Method 3b). Pure fractions were treated with a sat. aq. NaHCO 3 solution and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound as an off-white solid. The absolute configuration as depicted was confirmed by X-ray crystallography of the title compound in a complex with the ALK-2 kinase domain. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.57 (d, 2H), 7.23 (d, 2H), 6.92 (s, 2H), 4.31 (s, 1H), 3.91-3.78 (m, 2H), 3.40 (bs, 1H), 3.33-3.24 (m, 2H), 3.11 (d, 1H), 2.57 (bs, 1H), 2.50-2.34 (m, 1H), 2.34 (bs, 1H), 2.12-1.94 (m, 6H), 1.90-1.72 (m, 3H), 1.71-1.51 (m, 6H), 1.51-1.34 (m, 2H), 1.31 (t, 1H), 0.82-0.68 (m, 1H). (UPLC-MS) t R 0.54 min; ESI-MS 503 [M+H] +. Chiral HPLC (ChiralPak Id, 5 μm, flow rate: 1 mL/min, detection wavelength: 270 nm, mobile phase: heptane:isopropanol 60:40 (+0.1% diethylamine)): t R 18.7 min, 92.3% ee.

Alternative Example 34A: To a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid hydrochloride (1 kg, 1.683 mol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (343.9 g, 1.935 mol) in DMF (3500 mL) was added Et 3N (681.2 g, 6.732 mol) and HATU (767.9 g, 2.019 mol) at RT. The reaction mixture was stirred at RT for 1 h. The mixture was heated to IT=45° C., 5% NH 3.H 2O solution (5200 g) was added. Stirred for about 30 min, another 5% NH 3.H 2O solution (1800 g) was added. The mixture was heated to IT=45° C. for 2 h. The mixture was cooled to IT=22° C. Filtered, the wet cake was washed with H 2O (1500 mL×3). The wet cake was dried under vacuum at 45° C. for 24 h. The crude product was dissolved in acetone (3000 mL), then filtered to remove some undissolved solid. The filtrate was heated to IT=50° C. H 2O (2000 mL) was added. The mixture was stirred at IT=50° C. for 30 min until a white precipitate formed. H 2O (4000 mL) was added slowly. The mixture was stirred at IT=50° C. for 2 h. The mixture was cooled to IT=22° C. in 2 h, Filtered, the wet cake was washed with acetone:H 2O=1:2 (v/v, 1000 mL×2). The wet cake was dried under vacuum at 45° C. for 24 h. total 760 g white solid was obtained (89% yield, 99.4% ee).

1H NMR (DMSO-d6) δ: 8.32 (d, J=2.3 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.90 (s, 2H), 4.31 (s, 1H), 3.82 (m, 2H), 3.29 (m, 2H), 3.07 (d, J=8.5 Hz, 1H), 2.54 (d, J=8.3 Hz, 1H), 2.44 (dd, J=8.5, 3.5 Hz, 1H), 2.37 (m, 1H), 2.31 (td, J=10.2, 5.0 Hz, 1H), 2.04 (m, 6H), 1.80 (dt, J=7.9, 3.8 Hz, 1H), 1.71 (d, J=12.3 Hz, 1H), 1.65 (d, J=11.5 Hz, 1H), 1.62 (m, 6H), 1.38 (m, 1H), 1.34 (m, 1H), 1.29 (t, J=3.9 Hz, 1H), 0.73 (dd, J=7.9, 3.6 Hz, 1H).

13C NMR (DMSO-d6) δ: 167.80, 157.69, 148.28, 141.27, 134.91, 134.79, 126.40, 125.66, 123.53, 111.01, 66.22, 65.59, 59.10, 55.46, 52.04, 33.72, 31.92, 31.77, 30.59, 29.61, 24.14, 17.20.

MS(ESI-TOF): 503.3018 [M+H]+.

The starting material (hydrochloride salt) was obtained as follows:

Methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinate dihydrochloride (10 g, 19.5 mmol, 1.0 eq) was suspended in MeOH (31.7 g). A solution of NaOH (2.9 g, 72.2 mmol, 3.7 eq) in H 2O (10 g) was then added. The reaction mixture was heated to 45±5° C. and stirred for more than 3 h, yielding a suspension.

To another flask containing acetone (200 g), 5˜6 N HCl in i-PrOH (14.8 g, 97.6 mmol, 5 eq) was added. The solution was heated to 47±3° C. Then the above MeOH suspension was added to the mixture dropwise and stirred at 47±3° C. for 3 h. The mixture was cooled down to 23±3° C. and stirred for 3 h. After filtration, the wet cake was washed with acetone (40 g). The wet cake was dried under vacuum at 55° C. for 8 h. 2-Amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid hydrochloride (12.3 g, 99.3% HPLC purity, 62.1% assay yield) was obtained as an off-white solid.

1H NMR (DMSO-d6) δ: 11.53 (br s, 1H), 8.64 (br s, 1H), 8.54 (br s, 1H), 7.72-8.42 (m, 2H), 7.64 (br d, J=7.9 Hz, 2H), 7.38 (br d, J=7.8 Hz, 2H), 3.85-4.04 (m, 3H), 3.40-3.73 (m, 4H), 3.15-3.33 (m, 2H), 2.18 (br d, J=3.9 Hz, 1H), 1.95-2.12 (m, 4H), 1.88 (br d, J=10.0 Hz, 1H), 1.05 (br t, J=6.4 Hz, 1H).

13C NMR (DMSO-d6) δ: 167.2, 155.8, 144.3, 142.0, 139.6, 133.8, 127.7, 126.3, 124.1, 110.0, 65.8, 62.5, 55.7, 53.2, 29.9, 28.8, 28.7, 23.5, 16.6.

MS(ESI-TOF): 380.1974 [M+H] +.

The starting material, 2-Amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinate dihydrochloride, was obtained as follows:

To a 500 mL round bottom flask were charged 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-3-ium chloride (20 g, 1 eq), EA (200 mL), and 25% K 2CO 3 (62 g). The mixture was stirred for 30 min until all solids were dissolved. After phase separation, the organic layer was concentrated. 2-Methyl-2-butanol (48 g, 60 mL) was added. The organic layer was concentrated. 2-Methyl-2-butanol (144 g, 180 mL) was added.

The mixture was transferred to a 500 mL Redlay. K 2CO 3 (18.8 g, 2.5 eq) and methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (16.8 g, 1.04 eq; see Intermediate 1e) were added. The mixture was degassed with N 2 for three times. The mixture was heated to IT=50±5° C. within 1 h. Pd(dppf)Cl 2 (1.2 g, 0.03 eq) was added. The mixture was heated to IT=70±3° C. and stirred for 2 h. After cooling to 22° C., H 2O (120 g) and EA (180 g) were added and stirred for 30 min. MCC (6 g) was added and the mixture was filtered through MCC. The cake was washed with EA (54 g). After phase separation, the organic layer was washed with 5% NaCl (124 g). Quadrasil MP (Heavy metal scavenger from Johnson Matthey, 6 g) was then added to the organic layer. The mixture was heated to IT=55° C. for 8 h, filtered through MCC and washed with EA (54 g). Quadrasil MP (2 g) was added to the organic layer. The mixture was heated to IT=55° C. for 6 h, filtered through CMC and washed with EA (54 g). The organic layer was concentrated. Acetone (158 g, 200 mL) was added. After stirring at IT=22±3° C. for 30 min, the mixture was heated to IT=40±3° C. 15.5% HCl (38.4 g) was added dropwise with IT<50° C. The mixture was stirred at IT=45±3° C. for 1 h. The mixture was cooled to 22±3° C. The mixture was stirred at 22±3° C. for 1 h and filtered. The cake was washed with acetone (32 g×2). The wet cake was dried under vacuum at 50° C. for at least 8 h. The starting material was obtained, 22.5 g white solid (97.1% HPLC purity, 5.2% water content, 87% assay yield) was obtained.

1H NMR (DMSO-d6) δ: 11.43 (br d, J=5.7 Hz, 1H), 8.62-8.80 (m, 2H), 7.85-8.58 (m, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.85-4.06 (m, 6H), 3.60-3.69 (m, 2H), 3.50-3.59 (m, 1H), 3.44 (brd, J=7.7 Hz, 1H), 3.14-3.31 (m, 2H), 2.21 (dt, J=8.4, 4.2 Hz, 1H), 1.94-2.12 (m, 4H), 1.76-1.93 (m, 1H), 1.07 (br t, J=7.1 Hz, 1H).

13C NMR (DMSO-d6) δ: 165.0, 154.0, 143.5, 142.0, 140.1, 132.8, 127.7, 126.5, 124.2, 110.7, 65.8, 62.5, 55.6, 53.3, 53.3, 29.9, 28.9, 28.8, 23.6, 16.8.

MS(ESI-TOF): 394.2071 [M+H] +.

The starting material, 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-3-ium chloride, was obtained as follows:

To a 1 L Redlay were charged (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexan-3-ium chloride (30 g, 1 eq), dihydro-2H-pyran-4(3H)-one (13.13 g, 1.2 eq) and THF (300 mL). The mixture was stirred at IT=22±5° C. for 1 h. NaBH(OAc) 3 (30.1 g, 1.3 eq) was added portion wise while keeping IT<30° C. The mixture was stirred at IT=22±5° C. for 2 h. 6.2% HCl (93 g, 90 ml, 1.5 eq) was added while maintaining IT<30° C. and pH<2. The mixture was stirred for 10 min. 25% K 2CO 3 (259 g, 210 mL) was added to adjust pH=8-9. IPAc (300 mL) was added. The mixture was stirred for 10 min. After phase separation, H 2O (150 g) was added to the organic layer. The mixture was stirred for 10 min. After phase separation, the organic layer was concentrated under vacuum (50-100 mbar, 50° C. water bath). IPA (120 g, 150 mL) was added. The organic layer was concentrated under vacuum (50-100 mbar, 50° C. water bath). IPA (144 g, 180 mL) was added. The mixture was filtered through CMC. The cake was washed with IPA (24 g×2). H 2O (5 g) was added to the organic layer. 31% HCl (19.3 g) was added dropwise with IT<35° C. The mixture was stirred at IT=22±5° C. for 2 h and filtered. The cake was washed with IPA (48 g×2). The wet cake was dried under vacuum at 50° C. for at least 6 h. The desired product (31.4 g, 98% HPLC purity, 78% yield) was obtained as a white solid.

1H NMR (DMSO-d6 and D 2O) δ: 7.46 (br d, J=8.4 Hz, 2H), 7.15 (br d, J=8.4 Hz, 2H), 3.90 (br d, J=7.8 Hz, 3H), 3.62 (br s, 1H), 3.51 (br s, 2H), 3.16-3.38 (m, 3H), 2.05-2.21 (m, 1H), 1.93 (br s, 2H), 1.49-1.71 (m, 2H), 1.05-1.30 (m, 1H).

13C NMR (DMSO-d6) δ: 138.3, 131.9, 129.2, 120.4, 65.5, 62.3, 56.2, 53.9, 29.1, 28.9, 24.8, 23.0. MS(ESI-TOF): 322.0761 [M+H]+

 The complete way of manufacture of Alternative Example 34 A is depicted in the following Reaction Scheme 34A:

The first compound in this scheme, A1, can be obtained as follows:

Step 1-2 Synthesis of 1c and 1d

PAT

• Compound A [WO2021257532A1]

PAT

• example 34 [US20210155606A1]

PAT

US10710980, Example 34

PAPERS

• Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase-2 (ALK2) for the Treatment of Fibrodysplasia Ossificans ProgressivaPublication Name:ACS Medicinal Chemistry LettersPublication Date:2025-10-31PMCID:PMC12621050PMID:41256990DOI:10.1021/acsmedchemlett.5c00516
• Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy AdultsPublication Name:European Journal of Drug Metabolism and PharmacokineticsPublication Date:2024-12-09PMCID:PMC11802711PMID:39652202DOI:10.1007/s13318-024-00926-z

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References

1. "Atebrioz FDA label" (PDF). files.mirumpharma.com.
2. Gangat N, Tefferi A (June 2025). "Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes". American Journal of Hematology. 100 Suppl 4: 51–65. doi:10.1002/ajh.27659. PMID 40056069.
3. Center for Drug Evaluation and Research (25 September 2026). "FDA Approves Third Treatment for Fibrodysplasia Ossificans Progressiva". U.S. Food and Drug Administration. U.S. Food and Drug Administration (FDA). Retrieved 27 September 2026. This article incorporates text from this source, which is in the public domain.
4. "Mirum Pharmaceuticals and Incyte Announce U.S. FDA Approval of Atebrioz (zilurgisertib) for Adult and Pediatric Patients with Fibrodysplasia Ossificans Progressiva" (Press release). Mirum Pharmaceuticals. 25 September 2026. Retrieved 27 September 2026 – via Business Wire.
5. World Health Organization (2022). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88". WHO Drug Information. 36 (3). hdl:10665/363551.

External links

• "Zilurgisertib ( Code - C175551 )". EVS Explore.
• "Zilurgisertib Fumarate ( Code - C199021 )". EVS Explore.
• Clinical trial number NCT05090891 for "To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (Progress)" at ClinicalTrials.gov

Clinical data
Trade names	Atebrioz
Other names	INCB-000928, INCB000928
License data	US DailyMed: Zilurgisertib
Routes of administration	By mouth
Drug class	Kinase inhibitor (ALK2 selective)
ATC code	None
Legal status
Legal status	US: ℞-only[1]
Identifiers
CAS Number	2173389-57-42173390-29-7
PubChem CID	138628908162623634
IUPHAR/BPS	11888
UNII	L5Z9S25HO21R349830SB
KEGG	D12547D12548
ChEMBL	ChEMBL5314579
Chemical and physical data
Formula	C30H38N4O3
Molar mass	502.659 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

///////////zilurgisertib, anax labs, Atebrioz, FDA 2026, APPROVALS 2026, L5Z9S25HO2, INCB 000928

#zilurgisertib, #anax labs, #Atebrioz, #FDA 2026, #APPROVALS 2026, #L5Z9S25HO2, #INCB 000928

Tavapadon

 

Tavapadon

• CAS No.:1643489-24-0
• Formula:C₁₉H₁₆F₃N₃O₃
• Molecular Weight:391.34

9/25/2026, Juvmo, FDA 2026, APPROVALS 2026, CEREVEL, CVL 751, PF 6649751, PF-06649751,

To treat Parkinson’s disease in adults

Tavapadon (PF-06649751) is an orally active and highly selective dopamine D1/D5 receptor partial agonist. Tavapadon is effective in enabling movement and reducing disability and has the potential for Parkinson's disease.

Tavapadon (developmental code names CVL-751, PF-06649751) is a dopamine receptor agonist which is under development for the treatment of Parkinson's disease.^[2][3][4] It is under development by Cerevel Therapeutics, which acquired tavapadon from Pfizer in 2018.^[2] It is taken by mouth.^[1]

Tavapadon acts as a highly selective partial agonist of the dopamine D₁ receptor (K_i = 9 nM; IATooltip Intrinsic activity = 65%) and the dopamine D₅ receptor (K_i = 13 nM; IA = 81%).^[3][4][1] It has no significant affinity or functional activity at the D₂-like receptors (D₂, D₃, D₄) (K_i ≥ 4,870 to 6,720 nM).^[1] Tavapadon also shows biased agonism for G_s-coupled signaling at the D₁-like receptors.^[1][3]

As of December 2024, tavapadon has completed phase 3 clinical trials for Parkinson's disease.^[2]

• OriginatorPfizer
• DeveloperCerevel Therapeutics; Pfizer
• ClassAntiparkinsonians; Small molecules
• Mechanism of ActionDopamine D1 receptor agonists; Dopamine D5 receptor agonists
• registrationParkinson's disease
• 01 Dec 2025Cerevel Therapeutics completes a phase III TEMPO-4 trial in Parkinson Disease (In adults, In elderly in the US, Australia, Bulgaria, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Serbia, Spain, and Ukraine (PO) (NCT04760769)
• 28 Nov 2025No recent reports of development identified for phase-I development in Parkinson's-disease(In volunteers) in USA (PO, Tablet)
• 26 Sep 2025Preregistration for Parkinson's disease (Early-stage disease, In the elderly, In adults) in USA (PO)

The industrial synthesis of tavapadon typically proceeds via a convergent sequence:

1. Ether Formation: Coupling of a substituted phenol derivative (such as a 4-hydroxy-2-methylphenyl component) with a 2-halogenated-3-(trifluoromethyl)pyridine (e.g., 2-chloro-3-trifluoromethylpyridine) via nucleophilic aromatic substitution ($S_NAr$) or transition-metal-catalyzed cross-coupling to construct the biaryl ether framework.
2. Pyrimidine Ring Construction / Functionalization: Assembly or modification of the 1,5-dimethylpyrimidine-2,4-dione core onto the substituted aryl backbone, often utilizing base-catalyzed cyclizations (e.g., using methylating agents and urea/amide derivatives).
3. Chiral Resolution / Final Purification: Final isolation of the target enantiomer or specific crystalline form (as outlined in WO2023102087A1 and WO2023143321) to meet active pharmaceutical ingredient (API) regulatory grades.

PAT

W02014207601

Examples 7 and 8 

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014207601&_cid=P12-MUKNR1-83868-1

Step 1. Synthesis of tert-butyl 4-bromo-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (C22).

Compound C2 (800 mg, 3.65 mmol), di-tert-butyl dicarbonate (99%, 966 mg, 4.38 mmol), triethylamine (0.62 mL, 4.4 mmol) and 4-(dimethylamino)pyridine (45 mg, 0.36 mmol) were combined in tetrahydrofuran (15 mL) and heated to 70 °C for 1 hour, then allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was purified via chromatography on silica gel (Gradient: 10% to 25% ethyl acetate in heptane) to provide the product as a white solid. Yield: 1.10 g, 3.45 mmol, 94%. ¹H NMR (400 MHz, CDCl₃) δ 3.64 (s, 3H), 2.12 (s, 3H), 1.61 (s, 9H).

Step 2. Synthesis of ten-butyl 4-[4-(benzyloxy)-2-methylphenyl]-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate ( C23).

A mixture of C22 (1.00 g, 3.13 mmol), [4-(benzyloxy)-2-methylphenyl]boronic acid (98%, 1.16 g, 4.68 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) - tert-butyl methyl ether adduct (S-Phos precatalyst) (119 mg, 0.156 mmol), and cesium carbonate (3.06 g, 9.39 mmol) in 2-methyltetrahydrofuran (10 mL) and water (3 mL) was heated at 50 °C for 66 hours. The reaction mixture was diluted with water and ethyl acetate, and then filtered to remove suspended solids. The filtrate was extracted several times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in a 1:3 mixture of ethyl acetate and heptane, stirred for several minutes, and filtered, providing the product as a white solid. Yield: 970 mg, 2.22 mmol, 71%. LCMS m/z 337.2 [(M-Boc)+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.48 (m, 5H), 6.91-7.01 (m, 3H), 5.10 (s, 2H), 3.01 (s, 3H), 2.16 (br s, 3H), 1.66 (s, 9H), 1.64 (s, 3H).

Step 3. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C24).

Racemate C25 (1.30 g, 3.32 mmol) was separated into its atropenantiomers via chiral chromatography (Column: Phenomenex Lux Cellulose-2; Gradient: heptane / ethanol). The first-eluting atropenantiomer, obtained as a tan solid that exhibited a negative (-) rotation, was designated as Example 7. Yield: 536 mg, 1.37 mmol, 41%. The second-eluting atropenantiomer, also obtained as a tan solid but with a positive (+) rotation, was designated as Example 8. Yield: 553 mg, 1.41 mmol, 42%. 7: LCMS m/z 392.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (ddq, J=4.9, 1.9, 0.6 Hz, 1H), 8.30 (br s, 1H), 8.05 (ddq, J=7.6, 1.9, 0.7 Hz, 1H), 7.13-7.21 (m, 4H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H). 8: LCMS m/z 392.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (br d, J=4.9 Hz, 1H), 8.30 (br s, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.13-7.22 (m, 4H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H).

PAT

WO2015162084 SIMILAR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015162084&_cid=P12-MUKNEL-70374-1

PAT

US9334247

PAT

WO2023102087A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023102087&_cid=P12-MUKNKO-77090-1

Tavapadon, 1 , 5-dimethy I -6-(2-methy 1 -4- { [3 -(tri fluoromethyl)pyri din-2-yl]oxy}phenyl)pyrimidine-2,4(lH,3H)-dione has the following chemical structure:

and is described in International Publication No. W02014/207601. As disclosed in International Publication No. W02014/207601, the class of compounds encompassing Tavapadon, may exist as conformational isomers due to hindered rotation about a single bond, i.e., atropisomerism. In the case of Tavapadon, the atropenantiomers or atropisomers may be designated as (-)-Tavapadon or (+)-Tavapadon, depending on the optical rotation, and can include any mixture thereof, including a racemic mixture, wherein the racemic mixture can be designated as (±)-Tavapadon. According to International Publication No.

W02014/207601, the compound Tavapadon may be obtained as a racemate (i.e., (±)-Tavapadon), which may be separated by chiral chromatography into two atropenantiomers. The atropisomer exhibiting an anticlockwise (negative) rotation on a polarimeter is denoted the (-)-atropenantiomer [i.e., (-)-Tavapadon], and the atropisomer exhibiting a clockwise (positive) rotation on a polarimeter is denoted the (+)-atropenantiomer [i.e., (+)-Tavapadon],

PAT

WO2023143321 (or corresponding US20250145588A1 / CN115974803A equivalents)

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References

Clinical data
Other names	CVL-751; PF-6649751; PF-06649751
Routes of administration	By mouth[1]
Drug class	Dopamine receptor agonist
Identifiers
IUPAC name
CAS Number	1643489-24-0
PubChem CID	86764100
ChemSpider	48062699
UNII	PT4P8MJP8L
KEGG	D11431
ChEMBL	ChEMBL3697617
CompTox Dashboard (EPA)	DTXSID301337071
Chemical and physical data
Formula	C19H16F3N3O3
Molar mass	391.350 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1. Bezard E, Gray D, Kozak R, Leoni M, Combs C, Duvvuri S (2024). "Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease". CNS Neurol Disord Drug Targets. 23 (4): 476–487. doi:10.2174/1871527322666230331121028. PMC 10909821. PMID 36999711. Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors, [52] with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data). Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data). Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data). [...] In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine's intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).
2. "Tavapadon - Cerevel Therapeutics". Adis Insight. Springer Nature Switzerland AG.
3. Cerri S, Blandini F (December 2020). "An update on the use of non-ergot dopamine agonists for the treatment of Parkinson's disease". Expert Opinion on Pharmacotherapy. 21 (18): 2279–2291. doi:10.1080/14656566.2020.1805432. PMID 32804544. S2CID 221163451.
4. Hall A, Provins L, Valade A (January 2019). "Novel Strategies To Activate the Dopamine D₁ Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation". Journal of Medicinal Chemistry. 62 (1): 128–140. doi:10.1021/acs.jmedchem.8b01767. PMID 30525590. S2CID 54469910.

////////tavapadon, anax labs, Juvmo, FDA 2026, APPROVALS 2026, CEREVEL, CVL 751, PF 6649751, PF-06649751, 

#tavapadon, #anax labs, #Juvmo, #FDA 2026, #APPROVALS 2026, #CEREVEL, #CVL 751, #PF 6649751, #PF-06649751,