Exploration of Alternative Scaffolds for P2Y₁₄ Receptor Antagonists Containing a Biaryl Core

Abstract

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y 14 receptor (P2Y 14 R) antagonists were synthesized, and affinity was measured in P2Y 14 R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y 14 R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC 50 ≈ 20 nM at hP2Y 14 R/mP2Y 14 R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y 14 R antagonist structure−activity relationship, introducing diverse physical−chemical properties.

Structure–Activity Relationship of Heterocyclic P2Y14 Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres

“…The P2Y 14 receptor (P2Y 14 R) is a target for the treatment of inflammatory diseases, including pulmonary and renal conditions, and selective P2Y 14 R antagonists have demonstrated efficacy in animal models of asthma, pain, diabetes, and acute kidney injury. − Its endogenous agonists are uridine-5′-diphosphoglucose (UDPG) and other UDP-sugars, and UDP itself acts as a partial agonist. This G i protein-coupled receptor is one of three P2Y 12 R-like receptors in purinergic signaling pathways .…”

“…Various P2Y 14 R antagonists have been reported, and the most well explored class is derived from 7-phenyl-2-naphthalenecarboxylic acid. ,,− CHANGE REFS. 11-13 to 11-14.…”

“…11-13 to 11-14. Although there is no report yet of a P2Y 14 R X-ray crystallographic structure, we have applied a structure-guided approach using homology modeling and molecular dynamics (MD) simulation to the design of new antagonist ligands. ,, The nucleotide agonist-bound P2Y 12 R structure serves as a suitable protein template for P2Y 14 R homology, with 44% sequence identity between P2Y 12 R and P2Y 14 R. ,, Previous studies have analyzed the structure–activity relationship (SAR) of high affinity antagonist 4-[4-(4-piperidinyl)­phenyl]-7-[4-(trifluoromethyl)­phenyl]-2-naphthalene-carboxylic acid (PPTN, 1a , Chart ) and its analogues, e.g., potent N -acetyl derivative 1b and triazole derivatives 3a , 4 , and 5 . ,,,,, Compound 1a is a highly selective antagonist for the P2Y 14 R among the family of eight P2YRs; this chemical series has no evidence of an interaction with other P2YRs or of residual receptor agonism. , Therefore, we consider this to be a viable, high affinity scaffold for the design of new P2Y 14 R antagonists. As a screening tool, we previously introduced a high affinity fluorescent antagonist 2 , which shows a functional K i of 80 pM and serves as a versatile screening tool in a flow cytometry assay using Chinese hamster ovary (CHO) cells overexpressing the human (h) P2Y 14 R and human embryonic kidney (HEK)­293 cells overexpressing the mouse (m) P2Y 14 R. ,, Consistently reproducible IC 50 values can be obtained for newly synthesized antagonists, although these inhibitory constants underestimate the compounds’ affinity by at least one order of magnitude …”

Purinergic Signaling in Liver Pathophysiology

“…Future studies using liver-specific KO mouse models for understanding liver diseases are warranted. Numerous potent ligands for purinergic receptors have been synthesized that can be tested in preclinical mouse models of liver diseases (96)(97)(98)(99)(100)(101)(102)(103). Characterization of agonists and antagonists for purinergic receptors in preclinical mouse models may foster the development of novel drugs for the treatment of liver diseases.…”

Synthesis of ortho-Diamino-Functionalized 1-Arylnaphthalenes through Nickel-Catalyzed Cyclization of Ynamide-Benzylnitriles with Organoboronic Acids

“…They are also widely utilized in materials and as the ligands for catalysis such as BINAP. Among various derivatives, 1-arylnaphthalenes exist in a number of natural products such as 1-arylnaphthalene lignan lactones and have been shown to exhibit a wide range of biological activities such as phosphodiesterase inhibition, hypolipidemic (TA-7552), antitumor, P2Y 14 receptor antagonists (PPTN), and antiviral (helioxanthin); additionally they are also effective intermediates in the synthesis of 1-arylnaphthalene lignans. ,, Representative bioactive 1-arylnaphthalenes are depicted in Figure .…”