Elizabeth Margaret Moir

A novel series of positive modulators of the AMPA receptor: discovery and structure based hit-to-lead studies.

Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

Structure based evolution of a novel series of positive modulators of the AMPA receptor

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.

A novel series of positive modulators of the AMPA receptor: structure-based lead optimization.

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists.

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.

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.