D. Jonathan Bennett

An update on non-steroidal liver X receptor agonists and their potential use in the treatment of atherosclerosis

The liver X receptor (LXR)-α and -β isoforms are nuclear transcription factors that regulate the expression of a number of genes involved in lipid modulation. One key LXR target gene, which may offer therapeutic potential in the treatment of atherosclerosis, is the ATP-binding cassette transporter A1 (ABCA1) as it is involved in the process of reverse cholesterol transport. ABCA1 initiates the efflux of cholesterol from macrophages present in the atherosclerotic plaques of the arterial wall, where it is accepted by apolipoproteins such as apoA-1 and becomes high-density lipoprotein (HDL). HDL is then transported back to the liver for metabolism and excretion. A number of other genes are regulated by LXR function that may have positive or negative effects on atherosclerosis. Extrapolating the effect of individual gene regulation to an overall effect in humans, when all genes are modulated, is extremely difficult. This is further complicated by the fact that most preclinical work has been carried out in mice that differ quite significantly from humans in terms of lipid balance and metabolism. This review provides an update to the authors’ earlier patent review in this journal, which focused on the structural and biological data reported for LXR agonists in patent applications and associated literature. Various therapeutic indications have been reported for LXR agonists, but this review focuses solely on non-steroidal LXR agonists for the potential treatment of atherosclerosis.

A facile synthesis of N-benzylallylglycine

Abstract N -Benzylallylglycine can be prepared in good yield through a one-pot reaction of N -benzylhomoallylamine with glyoxylic acid monohydrate in methanol. The reaction method described requires only mild conditions and avoids the need for purification of the amino acid product.

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

Novel water soluble 2,6-dimethoxyphenyl ester derivatives with intravenous anaesthetic activity.

A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.

Liver X receptor agonists as a treatment for atherosclerosis

The liver X receptor (LXR)α and β isoforms are members of the Type II nuclear receptor family that function as heterodimers with the retinoid X receptor (RXR). Upon agonist binding, the DNA binding domain (DBD) of LXR interacts with LXR response elements on target genes to initiate transcription. The ATP-binding cassette transporter ABCA1 is an LXR target gene, which is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to high-density lipoproteins (HDL) in the plasma. Decreased levels of HDL are pro-atherogenic and, as such, increasing RCT by LXR agonism is a potential therapeutic mechanism for the treatment of atherosclerosis. A number of other genes are upregulated by LXR activation and may have positive or negative effects on atherosclerosis. One such target gene is sterol regulatory element binding protein (SREBP)-1c, which is involved in the process of lipogenesis leading to increased levels of triglycerides, which are pro-atherogenic. This review focuses on the structural and biological data reported for LXR agonists that have been claimed for the treatment of atherosclerosis in patent applications and associated literature. A brief reference is made to patent applications claiming the use of LXR agonists for other therapeutic indications. The importance of the interactions made between LXR agonists and the LXR ligand binding domain (LBD), which have been highlighted in recent X-ray crystallographic publications are also discussed.

Enantiospecific enzyme-catalysed resolution of novel N,N-disubstituted α-amino acid phenolic ester derivatives using pig liver esterase

R-Amino acid esters 1, 2 and 3 are novel compounds possessing hypnotic activity. On attempting an asymmetric synthesis of these molecules, racemisation was observed when reacting bis(2-methoxyethyl)amine with α-bromo intermediate 4. In vitro plasma stability studies showed that the R enantiomers had much greater resistance to esterase-mediated degradation than the corresponding S enantiomers. This observation led to the use of commercially available pig liver esterase to prepare 1, 2 and 3 on a multigram scale. The crystal structures of 1 and 2 are reported and confirm R configuration.