Design, synthesis and SAR of analgesics

A series of 4-phenylamidopiperidines having various substituents at the 4-position of the piperidine ring and the piperidine nitrogen were synthesized and tested. The antinociceptive activity of these compounds was measured by a modified hot-plate test. The active 4-phenylamidopiperidines have ED50 values ranging from 0.44 to 59 mg/Kg. High potency was observed among those compounds having an aralkyl substituent on the piperidine ring nitrogen. The highest Therapeutic Index value (TI = 223) was observed with N-[4-phenyl-1-(2-phenethyl)-4-piperidyl]-N-phenylpropanamide. Parameter Focusing using the regional fragment constants for the N-piperidine substituent (fL) and the C-4 piperidine substituent (fR') was successfully employed. The nature of the N-piperidine substituent is critical for activity, with the ideal fLo value at approximately 2.40. Structure-Activity Relationships indicate that the desired substituents for maximum enhancement of analgesic activity are an unsubstituted aromatic ring two carbons removed from the piperidine ring nitrogen and a small polar group able to hydrogen bond as a proton acceptor at the C-4 of the piperidine ring.