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  • Compounds and were synthesized according

    2021-06-17

    Compounds and () were synthesized according to . Reductive amination 5720 of ethyl acetoacetate with aniline afforded ester . Saponification of followed by intramolecular Friedel–Crafts acylation afforded ketone . Amide formation with benzoyl chloride followed by a reductive amination yielded compound . Finally, compound was obtained from acetamide formation of with acetyl bromide. Compounds and were obtained from reductive amination of with the appropriate aldehydes followed by acetamide formation. Compound was a key intermediate needed to enable facile exploration of the 1- position of tetrahydroquinoline (, ). Synthesis of started with the protection of at 1- position by Cbz to give carbamate (). Acetamide formation () and removal of Cbz delivered . Final derivatization (reductive amination, sulfonylation or acylation) at 1- position afforded compounds . The lead optimization was guided by H-PGD displacement assays using hCRTH2 stably transfected 293 cells in buffer solution and plasma. We evaluated most compounds as racemic mixtures and only resolved the enantiomers for compounds of interest. Modification of the acetyl group of the 4-phenylamino of showed that amides (e.g., , and ) were preferred over secondary amine , tertiary amine and sulfonamide (). A 3-carboxylpropionyl group significantly increased the binding affinity (). The corresponding amide () of carboxylic 5720 was less potent. The optimal distance between the acid and the amide carbonyl is two carbons, as in compound . Either shortening () or extending the distance () decreased the CRTH2 activity. The activity is also sensitive to the composition of the linker between the acid and the amide. Other linkers, such as acetylene () and 1,3-phenylene (), significantly reduced the binding affinity compared to the ethylene linker (). The aniline moiety at the 4-position of the tetrahydroquinoline core was studied briefly (). It was found that replacement of the phenyl of by a hydrogen () or a small alkyl group (), or extension of the phenyl by one methylene () all significantly decreased the CRTH2 activity. Variation at 1- position of the tetrahydroquinoline core () demonstrated that a bulk at 1- position was required for activity, as the compound () with no attachment at the position had little affinity for the CRTH2 receptor. In addition, the carbonyl of the benzoyl group () was preferred over a methylene () and a sulfonyl group (). Extending the benzene of the benzoyl group from the carbonyl () by one or two atoms (, and ) resulted in decrease of the CRTH2 activity. The medium size -alkyl amides, such as -butyl amide (), were also not as potent as the parental compound (). The substitution effect on the phenyl ring of the 1- benzoyl moiety is shown in . Compounds with methyl substitution at the and positions ( and ) displayed better potency than the -substituted analog (). 3,4-Dimethyl compound () was similar in potency to that of mono or -methyl compounds ( and ). In general, substitutions at the position afforded compounds with good CRTH2 binding affinity regardless of electronic and steric effects (, –). Some substitutions, such as phenoxy (), methoxy () and trifluoromethoxy (), at the -position yielded more potent compounds compared to the unsubstituted compound (). Based partially on their binding affinity, compounds , and were selected and resolved by chiral HPLC and each enantiomer was evaluated (). Like compound , the (2,4) enantiomers had greater affinity for the CRTH2 receptor. Even in the presence of plasma, these (2,4) enantiomers displayed strong inhibitory activity for the CRTH2 receptor. In addition to having high affinity for the CRTH2 receptor, these compounds are also potent functional antagonists. Compounds , , and were potent inhibitors of PGD-mediated human eosinophil shape change (). In particular, compound had an IC of 0.77nM. The affinity of these compounds for the DP receptor was evaluated with a H-PGD displacement assay using 293 cells stably transfected with hDP receptor. These compounds were found to be selective for the CRTH2 receptor over DP.