The mechanism of racemisation of 5-substituted hydantoins in aqueous solution

This thesis describes our studies of the racemisation of substituted hydantoins and is divided in six chapters. Chapter 1 presents the concepts of chirality and racemisation and its implications in drug development. The literature on the stereolability of 5-substituted hydantoins is summarised. Chapter 2 describes detailed kinetic and mechanistic studies of the racemisation of (5)-5-benzylhydantoin and (5)-3-iV-methyl-5-benzylhydantoin, aimed at establishing the mechanistic aspects of racemisation of these molecules. Kinetics of H/D exchange and racemisation, kinetic isotope effects, and solvent kinetic isotope effects all favour the SeI mechanism of racemisation as opposed to the Se2 process proposed by others. Chapter 3 discusses the effects of structural modifications on the stereolability of a series of model 5-substituted hydantoins with improved water solubility as compared to (iS)-5-benzylhydantoin and (5)-3-A-methyl-5-benzylhydantoin. Hydantoins containing a protonated amino or an ammonium group showed increased stereolability. This finding was attributed to intramolecular facilitation of racemisation by the positive charge. The primary and solvent kinetic isotope effects on the racemisation of two model 5-substituted hydantoins were determined and again supported an SeI mechanism of racemisation. Chapter 4 deals with solvent effects on racemisation and H/D exchange of a series of 5-benzylhydantoins. DMSO added to phosphate buffers showed a marked rate-increasing effect for all of the substrates under study. Co-added 2-propanol and dioxane showed a rate-decreasing effect on neutral hydantoins and a rate-increasing effect on a cationic hydantoin. Solvent effects on the basicity of anionic catalysts and phenomena of preferential solvation were proposed as important factors affecting the rate constants in mixed media. Chapter 5 reports the preliminary results of exploratory experiments aimed at assessing potentials and limitations of VCD and IR spectroscopy for kinetic and mechanistic studies of racemisation. Finally, Chapter 6 summarises our findings and presents recommendation for future work

The problem of racemization in drug discovery and tools to predict it

Introduction: Racemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas covered: Herein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and the authors review methods to predict racemization risk. Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinion: It is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline

Racemisation in chemistry and biology

The two enantiomers of a compound often have profoundly different biological properties and so their liability to racemisation in aqueous solutions is an important piece of information. We have reviewed the available data concerning the process of racemisation in vivo, in the presence biological molecules (e.g. racemase enzymes, serum albumin, cofactors and derivatives) and under purely chemical but aqueous conditions (acid, base and other aqueous systems). Mechanistic studies are described critically in light of reported kinetic data. The types of experimental measurement that can be used to effectively determine rate constants of racemisation in various conditions are discussed and the data they provide is summarised. The proposed origins of enzymatic racemisation are presented and suggest ways to promote the process that are different from processes taking place in bulk water. Experimental and computational studies that provide understanding and quantitative predictions of racemisation risk are also presented

Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain

An on-going trend in the medicinal chemistry literature is to link physical properties of a molecule that are achiral (such as lipophilicity) to biological or pharmaceutical properties (such as pharmacokinetics and toxicity) which depend upon interactions with chiral entities. In contrast, we have explored the variation in key pharmaceutical properties between enantiomeric pairs where only the three-dimensional arrangement of atoms changes. The analysis reveals that many properties are sensitive to changes in stereochemistry and quantifies this dependence. Any variation between enantiomers cannot be explained by achiral descriptors. The analysis highlights those properties where chiral lability or measurements on racemates might be misleading and permits deductions to be made from paired experiments in which two enantiomers are studied. The analysis suggests an inherent advantage to lead optimization in a chiral series where improvement into an attractive part of chemical space might be complemented by a selection between two enantiomers with different pharmacokinetic or safety profiles. Hence, in the early stages of a drug discovery program extra preference should be given to chiral series. Surprising observations are that permeability and efflux in cell based assays are not chirally dependent whereas in vivo volume of distribution does change between enantiomers