Simon Peace

The developability of heteroaromatic and heteroaliphatic rings – do some have a better pedigree as potential drug molecules than others?

Aqueous solubility, protein binding and CYP450 inhibition data for compounds containing a variety of heteroaromatic and heteroaliphatic rings were analysed and compared to determine which ring types fared best and worst in these developability screens. The results suggest that certain heterorings are generally more developable than others: how this information may be used and some caveats to be borne in mind are discussed.

Increasing small molecule drug developability in sub-optimal chemical space

Using compounds occupying four distinct clog P/molecular weight regions that define optimal and sub-optimal chemical space, and a developability score derived from solubility, permeability, protein binding and 3A4 inhibition screening data, OPLS regression models were constructed to determine which physico-chemical properties were most correlated with developability. The results suggested that whilst certain molecule properties were important for developability across all chemical space, such as [clog D + aromatic ring count], [clog D + (aromatic atom count – sp3 carbon count)] and [sp3 carbon count/total carbon count], others such as heteroaliphatic ring count, positive ionisable group count and H-bond donor character exhibited varying degrees of importance depending on the clog P/Mw region.

On the Diels–Alder reactions and the Lewis acid induced rearrangements of 6-fumaryl 1,3,8-nonatrienes

Abstract 6-Fumaryl 1,3,8-nonatrienes substituted at the C 5 position by a vinyl group were found to undergo competing tandem sigmatropic rearrangement/Diels–Alder cyclisation when heated under standard Diels–Alder cyclisation conditions. This rearrangement became the exclusive pathway when the reactions were performed in the presence of a Lewis acid.

Identification of a sulfonamide series of CCR2 antagonists.

A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.

Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease

A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.

In vivo activity of an azole series of CCR2 antagonists

Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 14 [corrected] which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation. [Formula: see text]. [corrected].