ABSTRACT
4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth.
Subject(s)
1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , Morpholines/pharmacology , Thiazoles/pharmacology , Animals , Combinatorial Chemistry Techniques , Drug Screening Assays, Antitumor , Humans , Isoenzymes , Mice , Molecular Structure , Morpholines/chemical synthesis , Morpholines/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
