Gergely M. Makara

The influence of lead discovery strategies on the properties of drug candidates

Despite the widespread acceptance of guidelines related to desirable physicochemical properties of potential small-molecule drugs, key properties — such as lipophilicity — of recently developed clinical candidates and advanced lead compounds have been shown to differ significantly from those of historical leads and drugs. By analysing the physicochemical properties of a large database of hits and corresponding leads identified in the past decade, we show that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices. Conceptual and organizational adjustments may be required to enable a smooth lead-evolution process that reduces the chance of high compound-related attrition in clinical trials.

Improving success rates for lead generation using affinity binding technologies.

Affinity technologies have been applied at several stages of the drug discovery process, ranging from target identification and purification to the identification of preclinical candidates. The detection of ligand–macromolecule interactions in lead discovery is the best studied and most powerful of these techniques. Although affinity methods have been in widespread use for about a decade, only recently have many reports emerged on their utility. Primary affinity screens of large libraries of small molecules or fragments have begun to produce results for challenging targets. Furthermore, in secondary assays affinity methods are opening new avenues to tackle important medicinal chemistry tasks.

A reagent-based strategy for the design of large combinatorial libraries: A preliminary experimental validation

Combinatorial library design can be carried out at either the reagent or the product level. Various reports in the literature have come to conflicting conclusions in favor of one over the other. In this paper a reagent-based screening library design strategy is presented. The method relies on analysis of scaffolds and building blocks separately to define the overall diversity in a compound file. The primary diversity selection by properties relevant for molecular recognition and by redundancy is followed by the application of filters for molecular properties known to be relevant for drug-likeness. Filter properties are rapidly estimated at the product level using a fragmental estimation approach. Initial experimental data suggest that high diversity in vast screening libraries can be achieved by carefully applied reagent level analysis. A potential role of diverse screening libraries in chemical genomics (pharmacological knockouts) is also discussed.

On the mechanism of the alkylation of quinoline and naphthyridine derivatives

Ethylation studies on substituted 3-ethoxycarbonyl-4-oxo-quinolines and -naphthyridines as well as of the potassium salts of their enolates has revealed that the pathway suggested by Frank et al. for the alkylation of 4-quinolone with (Et3O)PO, i.e., thermal rearrangement of an O- to N-alkyl product cannot be extended to this class of compound since no O-alkylated intermediates could be detected. The mechanism of the alkylation was revised and the site of attack was rationalised using Klopmans theorem and Pearsons HSAB (hard–soft acid–base) theory based on AM1 level semiempirical calculations. Our results suggest a nucleophile enolate intermediate, the alkylation of which can only lead to the N-alkylated product. In accordance with our calculations, the reactive enolates of the title compounds could be selectively transformed into the corresponding N-alkylated products. The selective formation of the N-alkylated product was explained by an analysis of the total charge distribution and frontier orbitals. The conclusions can be generalised for other alkylations.