title: 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.
abstract: Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Caroff
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Francis
authors.initials: F
authors.lastname: Hubler
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Dorte
authors.initials: D
authors.lastname: Renneberg
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Carmela
authors.initials: C
authors.lastname: Gnerre
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hilpert
authors.affiliation: Drug Discovery and Preclinical Research and Development, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Riederer
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077144:Clopidogrel; D004285:Dogs; D055808:Drug Discovery; D004951:Esterification; D006801:Humans; D008297:Male; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000188:drug therapy*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D002264:Carboxylic Acids; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058921:Purinergic P2Y Receptor Antagonists; D011759:Pyrrolidines; D000077144:Clopidogrel; D013988:Ticlopidine