1160271-35-1

Upstream product

• 128796-39-4 4-trifluoromethylphenylboronic acid 
• 1160270-01-8 ethyl 7-(4-(trifluoromethyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate 
• 1160269-99-7 ethyl 7-(4-(trifluoromethyl)phenyl)-4-hydroxy-2-naphthoate 
• 178876-99-8 7-Bromo-4-hydroxynaphthalene-2-carboxylic acid ethyl ester 
• 273727-44-9 4-(4-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 
• 1160270-14-3 ethyl 7-(4-(trifluoromethyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate 
• 1160271-34-0 tert-butyl 4-(4-(3-(ethoxycarbonyl)-6-(4-(trifluoromethyl)phenyl)naphthalen-1-yl)phenyl)piperidine-1-carboxylate 

Downstream Products

• 1160271-30-6 4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid 

Relevant academic research and scientific papers

Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-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 P2Y14R 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, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), 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 P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.

A selective high-Affinity antagonist of the P2Y14 receptor inhibits udp-glucose-stimulated chemotaxis of human neutrophilss

The nucleotide-sugar-Activated P2Y14 receptor (P2Y 14-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-Affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-Activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-R. We synthesized one of these molecules, a 4,7-disubstituted 2- naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y14-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a KB of 434 pM observed. In contrast, 1 mM PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11, P2Y12, or P2Y13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-Affinity antagonist of the P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems.

Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y14

Our series of competitive antagonists against the G-protein coupled receptor P2Y14 were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.

SUBSTITUTED 2-NAPHTHOIC ACIDS AS ANTAGONISTS OF GPR105 ACTIVITY

Substituted 2-naphthoic acids of structural formula I are effective as antagonists of the biological activity of GPR105 protein. They are useful for the treatment, control or prevention of disorders responsive to antagonism of this receptor, such as diabe