Molecular Determinants of the Platelet Aggregation Inhibitory Activity of Carbamoylpiperidines

Article abstract of DOI:10.1021/jm00094a004

A series of α,α'-bis<3-(N,N-dialkylcarbamoyl)piperidino>-p-xylenes were synthesized and tested for their inhibitory activity on ADP-induced aggregation of human platelets.A parabolic curve was obtained when log 1/C (activity) was plotted against log P (octanol/water partition coefficient).Using this as a model, a new analogue, α,α'-bis<3-(N-methyl-N-butylcarbamoyl)piperidino>-p-xylene (3g), was synthesized with a predicted IC50 of 25 μM.When this compound was subsequently evaluated, the IC50 was 22.1 +/- 5.5 μM, demonstrating the applicability of this model.The amide oxygen of the carbamoyl substituent appeared necessary for activity.Thus, for example, when the amide carbonyl group of 3a (IC50 = 44.5 μM) was reduced to CH2, the resulting compound 4 had a dramatically reduced activity, IC50 = 1565 μM.Compound 3a was resolved into (+) and (-) enantiomers and a meso (0) diastereomer using fractional crystallization, diastereomeric tartrate formation, and chiral HPLC.Compared to (-)-3a, the (+) isomer was 15 times more potent when ADP was the agonist and 19 times more active when collagen was used as the agonist.Molecullar modeling of R,R and S,S-3a using the SYBYL program was used to examine their interactions with phosphatidylinositol (PI).There was a better fit between PI and the R,R-3a with the energy of interaction being 17.6 kcal/mol less than that of S,S-3a/PI complex.Although the absolute stereochemistry of individual enantiomers is not known, this study shows that R,R-3a interacts more favorably with PI than does S,S-3a and that (+)-3a is a more potent inhibitor of human platelet aggregation than (-)-3a.It is postulated that because of their lipophilicity, these compounds penetrate the platelet membrane and are then protonated at the pH of the cytosol.The protonated N then neutralizes the anionic charge on the membrane phosphoinositides, thereby rendering them less susceptible to hydrolysis by phospholipase C.Thus, the determinant parameters for optimum antiplatelet activity in 3-carbamoylpiperidines are (1) the amide carbonyl, (2) appropriate stereochemistry of the 3-substituent and (3) a log P value of about 4.5.