Chiral drug potency: Pfeiffer's rule and computed chirality coefficients

Abstract Since the thalidomide tragedy there has been an increased awareness of the potential dangers in using racemic drugs. Pharmaceutical companies are required to justify each decision to manufacture a racemic drug in preference to its homochiral version. This process of justification is both time-consuming and costly. Any method for its simplification would be most valuable. The computer-aided molecular design method suggested here produces a sensitive quantitative structure activity relation between the eudismic ratios of drug enantiomers and a computed ‘chirality coefficient’ defined as (1 - molecular similarity). The advantage of this correlation is that it permits the explanation of previous experimental results and also the potency prediction of new drugs within a series.

[1]  K. Wilson,et al.  Chirality and its importance in drug development. , 1991, Biochemical Society transactions.

[2]  R. Barlow.  Enantiomers: how valid is Pfeiffer's rule? , 1990, Trends in pharmacological sciences.

[3]  Ramon Carbó,et al.  LCAO–MO similarity measures and taxonomy† , 1987 .

[4]  György G. Ferenczy,et al.  Semiempirical AM1 electrostatic potentials and AM1 electrostatic potential derived charges: A comparison with ab initio values , 1989 .

[5]  W. Graham Richards,et al.  Molecular similarity: The introduction of flexible fitting , 1990, J. Comput. Aided Mol. Des..

[6]  W. Graham Richards,et al.  Similarity of molecular shape , 1991, J. Comput. Aided Mol. Des..

[7]  Wilson H. De Camp,et al.  The FDA perspective on the development of stereoisomers. , 1989 .

[8]  C. Pfeiffer.  Optical isomerism and pharmacological action, a generalization. , 1956, Science.

[9]  E. J. Ariëns,et al.  CHOLINERGIC AND ANTICHOLINERGIC DRUGS, DO THEY ACT ON COMMON RECEPTORS? , 1967, Annals of the New York Academy of Sciences.

[10]  Shmuel Peleg,et al.  Two-dimensional rotational dynamic chirality and a chirality scale , 1990, Langmuir.

[11]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[12]  Ann M. Richard,et al.  Quantitative comparison of molecular electrostatic potentials for structure‐activity studies , 1991 .

[13]  B Testa,et al.  Racemates versus enantiomers in drug development: dogmatism or pragmatism? , 1990, Chirality.

[14]  Shmuel Peleg,et al.  Continuous symmetry measures , 1992 .