Evategrel

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Evategrel

CAS 2760609-74-1

MF C21H26ClNO7S MW 472.0 g/mol

(2Z)-2-[(4R)-1-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-(propan-2-yloxycarbonyloxymethylsulfanyl)piperidin-3-ylidene]acetic acid

(Z)-[(4R)-1-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-{[({[(propan-2-yl)oxy]carbonyl}oxy)methyl]sulfanyl}piperidin-3-ylidene]acetic acid
platelet aggregation inhibitor, CG-0255, CG 0255, 9FKJ76ZX22

Evategrel (CG-0255) is a promising new antiplatelet drug, a thioether prodrug, designed to improve upon clopidogrel (Plavix) by offering faster action, consistent potency, and overcoming resistance, with both oral and intravenous (IV) formulations available for emergency use. It works by rapidly converting to the same active metabolite as clopidogrel (H4) through simple hydrolysis, bypassing the CYP enzymes that can cause variability and resistance with clopidogrel. Clinical trials show it’s well-tolerated, potent, and has potential to become a superior P2Y12 inhibitor for preventing blood clots in cardiovascular conditions.

Key Features

Fast & Potent: Achieves significant platelet inhibition (IPA) within 15-30 minutes.
Consistent Activation: Relies on liver carboxylesterases, avoiding CYP2C19 variability, leading to less individual response difference.
Dual Formulation: First P2Y12 inhibitor with both IV (for emergencies/surgery) and oral forms.
Overcomes Resistance: Specifically designed to address clopidogrel resistance issues.
Low Drug-Drug Interactions: Expected to have minimal interactions.

How it Works

Prodrug: Evategrel is inactive when administered.
Hydrolysis: Liver esterase enzymes quickly break it down (hydrolyze it) in a single step.
Active Metabolite: This process creates H4, the same active antiplatelet molecule as clopidogrel’s active form.
Platelet Inhibition: H4 blocks the P2Y12 receptor on platelets, preventing them from clumping (aggregating).

Development & Potential

Developed by China-based CureGene.
Shows promise as a “best-in-class” P2Y12 antagonist, potentially benefiting patients with acute coronary syndromes (ACS) or those undergoing PCI (percutaneous coronary intervention).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023144782&_cid=P10-MKNELX-27983-1

Synthesis Example 1

Steps 11 and 12. Synthesize la-1 and la-2

The solution of 1–13 (1.8 g, 3.4 mmol) in TFA (10 mL) was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was added to a saturated NaHCO3 _solution (100 mL), followed by collection with EtOAc (100 mL * 3). The combined organic layers were washed with saturated NaHCO3 _, dried over Na2SO4 _, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (C18, CH3CN / _H2O = _80/20 ) to give la (550 mg, 34% yield). la was further purified by chiral column chromatography to give la-1 and la-2.

the:

LC-MS [M+l]+ = 472.1

57.59 (s, 1H), 7.38 (d, J = 4 Hz, 1H), 7.32-7.26 (m, 2H), 5.86 (s, 1H), 5.22 (dd, 12.2, 2.6 Hz, 1H), 5.00-4.83 (m, 3H), 4.50 (dd, J = 66.2, 11.9 Hz, 1H), 3.82 (s, 1H), 3.70 (d, J = 4.9 Hz, 3H), 3.52 (dd, J = 37.9, 12.9 Hz, 1H), 2.92-2.64 (m, 2H), 2.45-2.30 (m, 1 H), 1.95-1.84 (m, 1H), 1.30 ( 6.2 Hz, 6H)_O

la-1：

NMR (400 MHz, CDC1₃) 6 7.65 (s, 1H), 7.46 – 7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.7 Hz, 2H), 5.91 (s, 1H), 5.27 (d, J = 12.3 Hz, 1H), 5.04 – 4.87 (m, 3H), 4.49 (d, J = 13.7 Hz, 1H), 3.88 (s, 1H), 3.75 (s, 3H), 3.58 (d, J = 14.0 Hz, 1H), 2.87 (s, 2H), 2.44 (s, 1H), 1.95 (dd, J = 14.2, 3.3 Hz, 1H), 1.35 (d, J = 6.2 Hz, 6H)_O

la-2:

NMR (400 MHz, CDCh) 5 7.63 (s, 1H), 7.44 (dt, J = 8.2, 3.1 Hz, 1H), 7.35 – 7.31 (m,

2H), 5.92 (s, 1H), 5.25 (d, J = 12.3 Hz, 1H), 5.07 (s, 1H), 4.94 (td, J = 12.5, 6.5 Hz, 2H), 4.68 (d, J = 13.4 Hz, 1H), 3.87 (s, 1H), 3.76 (s, 3H), 3.50 (d, J = 13.4 Hz, 1H), 2.90 (s, 1H), 2.75 (d, J = 12.3 Hz, 1H), 2.44 (s, 1H), 1.96 (d, 7 = 13.2 Hz, 1H), 1.34 (d, J = 6.3 Hz, 6H) =

PAT