Medicinal Chemistry & Chemical Biology, Contributed Talk (15min)

Discovery and characterization of ACT-284069, a double prodrug of the P2Y12 receptor antagonist selatogrel

E. Caroff1, F. Hubler1, C. Gnerre1, A. Treiber1
1Idorsia Pharmaceuticals Ltd

Atherothrombotic conditions are currently managed by prescribing aspirin in combination with P2Y12 inhibitors. Approved oral P2Y12 antagonists include clopidogrel, prasugrel, and ticagrelor. We have previously disclosed the discovery of selatogrel (ACT-246475A), a new, potent, selective and reversible P2Y12 antagonist [1]. Selatogrel is currently in clinical development for early treatment of suspected acute myocardial infarction and is formulated for subcutaneous administration [2].

Based on the superior therapeutic window of selatogrel as compared to clopidogrel and ticagrelor in a rat thrombosis model [1,3], our initial goal was to develop a new efficacious oral treatment with less bleeding complications than standard of care. To address the low bioavailability of selatogrel observed after oral administration during preclinical animal studies, we embarked in an optimization program to design selatogrel prodrugs. Herein we report the synthetic efforts, the characterization cascade, and the data leading to the identification of the prodrug ACT-284069.

[1] Caroff, E.; Hubler, F.; Meyer, E.; Renneberg, D.; Gnerre, C.; Treiber, A.; Rey, M.; Hess, P.; Steiner, B.; Hilpert, K.; Riederer, M. A. 4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a novel P2Y12 receptor antagonist with a wider therapeutic window in the rat than clopidogrel. Med. Chem. 2015, 58, 9133–9153.
[2] a Storey, R.F.; Gurbel, P. A.; Ten Berg, J.; Bernaud, C.; Dangas, G. D.; Frenoux, J. M.; Gorog, D. A.; Hmissi, A.; Kunadian, V.; James, S. K.; Tanguay, J. F.; Tran, H.; Trenk, D.; Ufer, M.; Van der Harst, P.; Van't Hof, A. W. J.; Angiolillo, D. J. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Heart J. 2019, 10.1093/eurheartj/ehz807. b NCT04957719.
[3] Rey, M.; Kramberg, M.; Hess, P.; Morrison, K.; Ernst, R.; Haag, F.; Weber, E.; Clozel, M.; Baumann, M.; Caroff, E.; Hubler, F.; Riederer, M. A.; Steiner, B. The reversible P2Y12 antagonist ACT-246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat. Res. Per. 2017, 10.1002/prp2.338.