2128-87-2Relevant academic research and scientific papers
Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors
Zheng,Salgia,Thompson,Dillingham,Bond,Feng,Prasad,Gollamudi
, p. 180 - 188 (2007/10/02)
A detailed structure-activity analysis was carried out using eight 1- alkyl(aralkyl)nipecotamides (type 5), 33 bis-nipecotamidoalkanes and aralkanes (type 6), and 7 N,N'-bis(nipecotoyl)-piperazines (type 7) as inhibitors of human platelet aggregation. Steric factors played an important role in determining the activity of type 5 compounds possessing an appropriate degree of hydrophobic character. Types 6 and 7 compounds were more potent than the corresponding type 5 molecules. Hydrophobic character appeared to influence the activity of type 6 compounds. A 3-substituent on the piperidine ring was necessary for antiplatelet activity; the substituent should be preferably an amide with its C attached directly to the ring. 3,5- Disubstitution and 2-substitution led to a decline in activity. Optimal activity was attained when the two nipecotoyl ring N atoms were connected by an aralkyl group, and separated by ~7 ?. It is suggested that van der Waals forces and π interactions may govern the inhibitor-platelet interaction. The most potent type 6 inhibitor was α,α'-bis[3-(N-ethyl-N- butylcarbamoyl)piperidino]-p-xylene (6i). The most potent type 5 compound was 1-decyl-3-(N,N-diethylcarbamoyl)piperidine (5a). Any substitution on the piperazine ring of type 7 compounds led to a decline in activity, the most active analog being N,N'-bis(1-decylnipecotoyl)piperazine (7a). It is suggested that nipecotamides interact with anionic platelet sites located 7 ? from each other and connected by a hydrophobic well.
Molecular Determinants of the Platelet Aggregation Inhibitory Activity of Carbamoylpiperidines
Feng, Zixia,Gollamudi, Ramachander,Dillingham, Elwood O.,Bond, Stephen E.,Lyman, Beverly A.,et, al.
, p. 2952 - 2958 (2007/10/02)
A series of α,α'-bis-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-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.
