Stephen R. Mack

IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines.

Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.

IRAK-4 inhibitors. Part II: A structure-based assessment of imidazo[1,2-a]pyridine binding

A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.

IRAK-4 inhibitors. Part 1: a series of amides.

The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.

Synthesis of novel substituted isoquinolones

A series of novel substituted isoquinolones have been synthesised. This has been achieved by two routes, either Curtius rearrangment of cinnamic acids or via an isoquinoline N-oxide.

Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines

The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.

Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing

GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing.

Anti-hyperalgesic effects of a novel TRPM8 agonist in neuropathic rats: A comparison with topical menthol

&NA; An in vivo electrophysiological characterisation of the pro‐ and anti‐nociceptive effects of TRPM8 agonists reveals menthol and a novel TRPM8 agonist have selective inhibitory effects on cold sensitivity in neuropathic rats. &NA; Menthol has historically been used topically to alleviate various pain conditions. At low concentrations, this non‐selective TRPM8 agonist elicits a cooling sensation, however higher concentrations result in cold hyperalgesia in normal subjects and paradoxically analgesia in neuropathic patients. Through behavioural and electrophysiological means, we examined whether this back‐translated into a pre‐clinical rodent model. Menthol was applied topically to the hind paws of naive and spinal nerve‐ligated (SNL) rats. In behavioural assays, menthol did not affect withdrawal thresholds to mechanical stimulation and 10% and 40% menthol rarely sensitised withdrawals to innocuous cooling in naïve rats. However, in SNL rats, 10% and 40% menthol alleviated cold hypersensitivity. This was partly corroborated by in vivo electrophysiological recordings of dorsal horn lamina V/VI neurones. As several studies have implicated TRPM8 in analgesia, we examined whether a novel systemically available TRPM8 agonist, M8‐Ag, had more potent anti‐hyperalgesic effects than menthol in neuropathic rats. In vitro, M8‐Ag activates TRPM8, expressed in HEK293 cells, with an EC50 of 44.97 nM. In vivo, M8‐Ag inhibited neuronal responses to innocuous and noxious cooling in SNL rats with no effect in sham‐operated rats. This effect was modality selective; M8‐Ag did not alter neuronal responses to mechanical, heat or brush stimulation. In addition, M8‐Ag attenuated behavioural hypersensitivity to innocuous cooling but not mechanical stimulation. These data suggest that menthol induced hyperalgesia is not consistently replicable in the rat and that the analgesic properties are revealed by injury. Systemic TRPM8 agonists might be beneficial in neuropathy without affecting normal cold sensitivity.

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.