Identification of High-Affinity P2Y₁₂ Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

Abstract

A series of novel, highly potent P2Y₁₂ antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure-activity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y₁₂ antagonists displaying not only low nanomolar binding affinity to the P2Y₁₂ receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC₅₀ values below 50 nM. Using a homology and a three-dimensional quantitative structure-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

“…Several groups have synthesized numerous glutamic acid piperazine derivatives having P2Y 12 R antagonist activity (compounds 32 – 41 ) [16–20]. Such compounds have been developed through the molecular optimization of quinoline derivatives (such as (S)-4-({[4-(1-carboxy-1-methylethoxy)-7-methylquinolin-2-yl]carbonyl}amino)-5-[4-(ethoxycarbonyl)piperazin-1-yl]-5-oxopentanoic acid, BX048, structure not shown) [57].…”

“…Compounds 27 – 31 : radioligand binding assays with [ 3 H]PSB-0413 and human platelet membranes [15]. Compounds 32 – 41 : radioligand binding assays with [ 33 P]2MeSADP and hP2Y 12 R-transfected CHO cell membranes [16, 18, 20]. Compounds 44 – 47 : radioligand binding assays with [ 125 I] antagonist of the P2Y 12 R and washed human platelets [23].…”

“…However, considerable progress has been made in exploring the structure-activity relationship (SAR) of antagonists for the P2Y 12 subtype [1, 5]. P2Y 12 R agonists are essentially nucleotide derivatives [5, 8, 9] (compounds 1–8 , Chart 1), while several different chemical classes have shown P2Y 12 antagonist activity, including: ureas, sulfonylureas and sulfonamides [10–14]; anthraquinones [15]; glutamic acid piperazines [16–20]; nucleotide and nucleoside derivatives [21–28] and dinucleotides [29–31] (compounds 9–55 , Chart 2, Table 1). The currently used antithrombotic drugs clopidogrel ( 56 , Plavix) and prasugrel ( 57 , Effient) (Chart 3) belong to the thienopyridine class of P2Y 12 antagonists, which require metabolic activation in vivo prior to binding covalently to the receptor to induce an irreversible inhibition.…”

Recent Advances in the Development of P2Y12 Receptor Antagonists as Antiplatelet Agents

“…26 The compounds were based on a phenylpyrazole glutamic acid piperazine backbone (14). 26 The compounds were based on a phenylpyrazole glutamic acid piperazine backbone (14).…”

An Expedient Method for the Synthesis of 1,2,4‐Triazolo‐fused 1,5‐Benzodiazepine, 1,5‐Benzoxazepine, and 1,5‐Benzothiazepine Scaffolds: A Novel Seven‐membered Ring System of Biological Interest

“…These heterocycles are crucial pharmacophores for a variety of important chemical products, materials, pharmaceuticals (e.g., triazolam, alprazolam, etizolam, midazolam, and adinazolam) , and agrochemicals . These triazole‐condensed heterocyclic derivatives hold many medicinal applications like potent sedative, muscle relaxant, depression, psychoactive drug, hypnotic, anticonvulsant, antibacterial, and antifungal activities .…”