William Farnaby

Assessing molecular scaffolds for CNS drug discovery

There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood-brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs. Prospective use of this CNS Lead Multiparameter Optimisation (MPO) scoring protocol can guide the further development of novel synthetic methodologies to access CNS-relevant and lead-like chemical space.

Identification of compounds acting as negative allosteric modulators of the LPA1 receptor

Abstract The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1‐(4‐{4‐[3‐methyl‐4‐({[(1R)‐1‐phenylethoxy]carbonyl}amino)‐1,2‐oxazol‐5‐yl]phenyl}phenyl)cyclopropane‐1‐carboxylic acid (BMS‐986202) and 2‐{4‐methoxy‐3‐[2‐(3‐methylphenyl)ethoxy]benzamido}‐2,3‐dihydro‐1H‐indene‐2‐carboxylic acid (SAR‐100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4‐({(Cyclopropylmethyl)[4‐(2‐fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK‐615) with BMS‐986202 and SAR‐100842. Back‐scattering interferometry (BSI) was used to show that the apparent affinity of TAK‐615 was enhanced in the presence of LPA. The binding signal for BMS‐986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR‐100842 was also enhanced in the presence of LPA. Only BMS‐986202 was able to fully inhibit the response to LPA in calcium mobilisation, &bgr;‐arrestin, cAMP, GTP&ggr;S and RhoA functional assays. TAK‐615 and SAR‐100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK‐615 is not competitive with either SAR‐100842 or BMS‐986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK‐615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR‐100842 also behaves like a NAM. BMS‐986202 on the other hand behaves like an orthosteric antagonist.