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  • br P Y receptor structure br Pharmacology


    P2Y receptor structure
    Pharmacology Several subtype selective compounds have been developed in recent years (Jacobson and Müller, 2016; Rafehi and Müller, 2018). These compounds are helpful tools for analyzing the roles of P2Y receptor subtypes in physiology and pathophysiology. The present article summarizes pharmacological properties of the eight human P2Y receptor subtypes and discusses selective compounds.
    Declaration of conflicting interest
    Asthma is a complex, chronic inflammatory disease of the airways which affects around 300 million people worldwide, and is the most common chronic disease in children. Cysteinyl leukotrienes (LTC, LTD and LTE) are products of the 5-lipoxygenase pathway of arachidonic ICG001 metabolism which play a crucial role in asthma pathophysiology by causing bronchoconstriction, mucus production and increased vascular permeability. They exert their biological actions by activating two G-protein-coupled receptors called CysLT1 and CysLT2. CysLT1 receptor antagonists have been shown to be effective in the treatment of asthma and several compounds with this mechanism of action have reached the market in recent years. As part of an Almirall research programme for the design, synthesis and pharmacological evaluation of novel CysLT1 antagonists, the preparation of a series of tricyclic carboxylic acids () has been carried out. In order to prepare multigram quantities of these new anti-asthmatic compounds for further testing, an efficient synthesis of both enantiomers of compounds was developed. The first step in our synthetic approach towards acids in an enantiomerically pure form was the reaction of -cysteine ethyl ester hydrochloride with racemic alcohols to give the diastereoisomeric aminoesters and in a 1:1 ratio (). Although all attempts to separate diastereoisomers by crystallization failed, we were successful in separating them by crystallizating the corresponding mixtures of formamides and (easily prepared from aminoesters by reaction with HCOOEt). Deprotection of the formyl group by using EtOH/HCl/HO gave the desired isolated aminoesters and with de values >97% in all cases (measured by H NMR analysis). With the separation of diastereoisomers successfully accomplished in all three examples, our attention was then focused on the removal of the α-amino group. Deamination of aminoesters and , the key step in our synthetic approach towards enantiomerically pure acids , proved to be more difficult than anticipated. At this point, aminoesters and were transformed to the corresponding α-acetamidoesters, α-aminoacids and α-isonitriloesters and several methods for the reductive cleavage of such intermediates were explored without reward. Methods involving the reduction of both enantiomers of α-diazoesters (easily prepared by treatment of aminoesters and with isoamyl nitrite) were also studied with little success. Of these, only HI-mediated reduction of α-diazoesters, gave moderate yields of the desired deaminated products in just one of the examples () so a different approach for the cleavage of the amino group was needed. The key to the solution of our problems was found in a reaction reported by Bestmann and Kolm who observed that elimination of N from α-hydrazonoester was achieved under very mild conditions by treating this compound with a tertiary amine through a Wolff–Kishner type process (). With this result in mind, an alternative strategy for the deamination of aminoesters and was then investigated. This new approach was based on the conversion of our α-aminoesters into the corresponding α-hydrazonoesters in order to perform N elimination by treatment of such intermediates with a suitable base as described by Bestmann and Kolm. α-Hydrazonoesters could be prepared by selective reduction of α-diazoesters , intermediates already prepared in an enantiomerically pure form from aminoesters and .