• 2018-07
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  • 2019-08
  • br Conclusion The preclinical data reported in this study sh


    Conclusion The preclinical data reported in this study shows that LAS191859 is a potent and safe CRTh2 antagonist, with a long receptor residence time that provides a sustained in vivo efficacy. This property is reflected in the prolonged duration of action of LAS191859 in in vitro and in vivo functional models. The results presented here are the first to demonstrate that long receptor residence time in the CRTh2 receptor translates into a long-lasting efficacy in vivo and this efficacy is achieved in the absence of pharmacologically relevant systemic plasma levels.
    CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), also known as DP, is a G-protein coupled receptor related to the -formyl peptide receptor (FPR) subfamily of chemoattractant receptors. Its endogenous ligand is prostaglandin D (PGD). PGD is the major cyclooxygenase product formed and secreted by activated mast cells during allergic reactions., , PGD also signals through prostanoid D (DP or DP) receptor. The DP receptor is primarily expressed on airway epithelium, smooth muscle and platelets, while CRTH2 is selectively expressed on Th2 cells, T cytotoxic type 2 (Tc2) cells, eosinophils, and basophils., , Stimulation of CRTH2 by PGD mediates multiple inflammatory responses, such as chemotaxis of eosinophils, basophils and Th2 cells, eosinophil activation and degranulation, cytokine production from Th2 T cells, and leukotriene production by mast cells., , , , , , Therefore, blockade of CRTH2 is likely to be beneficial in the treatment of allergic diseases triggered by PGD. Several research groups, including ours, discovered that tetrahydroquinoline derivatives are potent CRTH2 antagonists., , , , , These compounds were of special interest to us, because to our knowledge, it was the only series of CRTH2 antagonists devoid of a carboxylic Measures moiety. Here we report the discovery, optimization and structure activity relationship (SAR) of the tetrahydroquinoline derivatives. Tetrahydroquinoline (), discovered in a high throughput screen, inhibited the binding of H-PGD to hCRTH2 receptors on 293 cells with an IC of 0.043μM (). Compound also inhibited CRTH2 mediated cell migration in response to PGD with an EC of 11nM using hCRTH2 stably transfected CEM cells. The structure of compound was determined to be by synthesis () and NMR studies. Conversely, the isomer () had weak CRTH2 activity. Furthermore, the stereo-selective synthesis () indicated the (2,4) enantiomer was responsible for the majority of the CRTH2 activity of racemic compound (). Compound was synthesized according to . Reaction of aniline with acetaldehyde in ethanol at room temperature afforded a mixture of isomers and in >95% yield. Separation of the isomers was achieved in 35% yield by recrystallization from 10% EtOAc/Hex. The isomer was obtained in 30% yield from the purification of the mother liquor using silica column chromatography. Selective acylation of and with benzoyl chloride at 1- position afforded amides and , respectively, in 90% yield. Reaction of and with acetyl chloride afforded and , respectively, in 85% yield. Compounds () were synthesized from intermediate using reductive amination, sulfonylation or acylation. The stereo-selective synthesis () of began with a CuI catalyzed coupling of iodobenzene with the ()-β-amino acid ester. Amide formation of the coupling product () with benzoyl chloride followed by ester hydrolysis yielded acid . Conversion of the carboxylic acid to the acid chloride followed by an intramolecular Friedel–Crafts acylation provided ketone . Reductive amination with ammonium hydroxide produced primary amine , which was coupled with phenyl boronic acid in the presence of copper acetate to give compound . Reaction of with acetyl bromide afforded compound ((2,4)-enantiomer) with >99% ee. Compound ((2,4)-enantiomer) was obtained from chiral HPLC separation of racemate .