Tebapivat

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Tebapivat

CAS 2283422-04-6

WeightAverage: 392.44
Monoisotopic: 392.116778341

Chemical FormulaC₁₈H₁₆N₈OS

10-[(6-aminopyridin-2-yl)methyl]-7-methyl-4-(1H-pyrazol-5-ylmethyl)-3-thia-5,7,10,11-tetrazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,11-tetraen-9-one
6-[(6-aminopyridin-2-yl)methyl]-4-methyl-2-[(1H-pyrazol-3-yl)methyl]-4,6-dihydro-5H-[1,3]thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5-one

6-[(6-aminopyridin-2-yl)methyl]-4-methyl-2-[(1H-pyrazol-3-yl)methyl]-4,6-dihydro-5H-[1,3]thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5-one

AG946
CS-0115951
HY-135884
ORG4KGP5ZS

OriginatorAgios Pharmaceuticals
ClassAntianaemics; Small molecules
Mechanism of ActionPyruvate kinase stimulants
Orphan Drug StatusYes – Myelodysplastic syndromes
Phase IIAnaemia; Sickle cell anaemia
01 May 2025Phase-II clinical trials in Sickle cell anaemia in USA (PO) (NCT06924970)
01 May 2025Agios plans to initiate a phase II clinical trial for Sickle cell disease(PO) in mid-2025.
21 Feb 2025Agios Pharmaceuticals completes a phase I bioavailability trial (In volunteers) in USA (PO, capsule) (NCT06745271)

Tebapivat is under investigation in clinical trial NCT05490446 (A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-risk Myelodysplastic Syndromes (LR-MDS)).

Tebapivat is an orally available activator of the red cell isoform of pyruvate kinase (PK-R; PKR), with potential to improve hemolytic anemia and related-symptoms in patients with pyruvate kinase deficiency (PKD). Upon oral administration, tebapivat binds to and activates PKR, thereby enhancing glycolytic pathway activity in red blood cells (RBCs), improving adenosine triphosphate (ATP) levels and reducing 2,3-diphosphoglycerate (2,3-DPG) levels. This may result in increased oxygen affinity, improved RBC deformability, decreased sickle RBC hemolysis, increased hemoglobin (Hb) levels and improved RBC membrane function. Mutations in PKR cause deficiency in PKR which prevents adequate RBC glycolysis, leading to a build-up of the upstream glycolytic intermediate 2,3-DPG and deficiency in the PKR product ATP.

SCHEME

COUPLER

COUPLER

MAIN

PATENT

Agios Pharmaceuticals, Inc.

WO2019035864

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019035864&_cid=P22-MDGSEF-03229-1

Example 8A. Synthesis of 2-((1H-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)- 4-methyl-4H-thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one and 6-((6- aminopyridin-2-yl)methyl)-4-methyl-2-(1H-pyrazole-3-carbonyl)-4H- thiazolo[5′,4′:4,5]pyrroIo[2,3-d]pyridazin-5(6H)-one

Step F. Synthesis of 6-((6-aminopyridin-2-yl)methyl)-4-methyl-2-(1H-pyrazole-3- carbonyl)-4H-thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one To a solution of tert- butyl (6-((4-methyl-5-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonyl)- 4H-thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-6(5H)-yl)methyl)pyridin-2-yl)carbamate (20 mg, 0.03 mmol) in EtOH (1 mL) was added HCl (1 mL, 4 mol/L in dioxane). The mixture was stirred at 80 °C for lhr and cooled down. The precipitate was collected by filtration and neutralized with sat. NaHCO₃, washed with water and dried to afford 5 mg of 6-((6- aminopyridin-2-yl)methyl)-4-methyl-2-(1H-pyrazole-3-carbonyl)-4H- thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one. LC-MS (ESI): m/z 407 (M+H)⁺. 1H NMR (400 MHz, DMSO-d₆) δ: 8.75 (s, 1H), 7.96 (s, 1H), 7.50 (s, 1H), 7.31-7.22 (m, 1H), 6.31 (d, 1H), 6.14 (d, 1H), 5.91 (s, 2H), 5.23 (s, 2H), 4.38 (s, 3H).

PATENT

WO2023091414

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023091414&_cid=P22-MDGSRV-15431-1

PATENT

WO2019035863

WO2019035865

WO2019035864