Amezalpat

CAS 1616372-41-8

MF C34H41N3O4 MW555.7 g/mol

• [1,1′-Biphenyl]-3-acetic acid, 3′-[3-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-ethyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]propyl]-4-ethoxy-
• 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
• 3′-(3-(1-((4-(1,1-DIMETHYLETHYL)PHENYL)METHYL)-4-ETHYL-4,5-DIHYDRO-5-OXO-1H-1,2,4-TRIAZOL-3-YL)PROPYL)-4-ETHOXY(1,1′-BIPHENYL)-3-ACETIC ACID

2-[5-[3-[3-[1-[(4-tert-butylphenyl)methyl]-4-ethyl-5-oxo-1,2,4-triazol-3-yl]propyl]phenyl]-2-ethoxyphenyl]acetic acid

peroxisome proliferator-activated receptor alpha (PPARα) antagonist, antineoplastic, TPST 1120, FDA Fast Track,  Orphan Drug, 1EQ4LQN9N3

Amezalpat (formerly TPST-1120) is an investigational, oral, small-molecule inhibitor targeting peroxisome proliferator-activated receptor alpha (PPAR being developed by Tempest Therapeutics. It works by directly targeting tumor cells and reducing immune suppression in the tumor microenvironment. In combination with atezolizumab and bevacizumab, it has shown improved survival in hepatocellular carcinoma (HCC) patients, receiving FDA Fast Track and Orphan Drug designations. 

Key Details on Amezalpat

• Indication: Primarily being studied for unresectable or metastatic hepatocellular carcinoma (liver cancer).
• Mechanism: A selective, competitive antagonist of PPAR$$, which plays a role in fatty acid metabolism in cancer cells.
• Clinical Efficacy: A phase 1b/2 study indicated that adding amezalpat to standard-of-care (atezolizumab + bevacizumab) improved median overall survival to 21 months compared to 15 months for the control, according to Tempest Therapeutics.
• Trial Status: A pivotal Phase 3 study (NCT06680258) to evaluate this combination as a first-line treatment is planned for 2025.
• Other Potential Uses: Preclinical data suggests potential activity in other advanced solid tumors, including renal cell carcinoma. 

Disclaimer: Amezalpat is an investigational agent and is not yet approved by the FDA for widespread clinical use.

Amezalpat is an orally bioavailable, small molecule, selective and competitive antagonist of peroxisome proliferator activated receptor alpha (PPARa), with potential immunomodulating and antineoplastic activities. Upon oral administration, amezalpat targets, binds to and blocks the activity of PPARa, thereby blocking transcription of PPARa target genes leading to an intracellular metabolism shift from fatty acid oxidation (FAO) to glycolysis in FAO-dependent tumors and reducing the production of fatty acids in the tumor microenvironment (TME). As fatty acids are essential for tumor cell growth in FAO-dependent tumor cells and are needed for the metabolism of suppressive immune cells in the TME, including regulatory T-cells (Tregs), reducing the amount of fatty acids leads to a direct killing of FAO-dependent tumor cells. It also skews macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells, thereby stimulating an anti-tumor immune response and further killing tumor cells. Amezalpat also restores the natural inhibitor of angiogenesis thrombospondin-1 (TSP-1) and stimulator of interferon genes (STING) in the TME. PPARa, a ligand-activated nuclear transcription factor and metabolic checkpoint, regulates the expression of FAO genes and lipid metabolism. It plays a key role in immunosuppression in the TME. FAO is a metabolic pathway essential to tumor growth, survival and immunosuppression.

SYN

US20240041837,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US421389770&_cid=P12-MNCKHO-56782-1

Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid

SYN

US20240041837,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US421389770&_cid=P12-MNCKLO-59107-1

SYN

WO2014099503 TRIAZOLONE COMPOUNDS AND USES THEREOF

Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1, 1′-biphenyl]-3-yl)acetic acid

Pat

WO2025235527 CRYSTALLINE FORMS OF A PPAR ALPHA ANTAGONIST

2-(3′-(3-(l-(4-(tertbutyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,T-biphenyl]-3-yl)acetic acid, depicted below as Compound A

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/////////////amezalpat, ANAX LAB, antineoplastic, TPST 1120, FDA Fast Track,  Orphan Drug, 1EQ4LQN9N3