Discovery, synthesis and biological evaluation of a series of N-(phenylcarbamothioyl)-2-napthamides as inhibitors of Claudin-1.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, despite advancements in diagnosis. The main reason for this is that many newly diagnosed CRC patients will suffer from metastasis to other organs. Thus, the development of new therapies is of critical importance. Claudin-1 protein is a component of tight junctions in epithelial cells, including those found in the lining of the colon. It plays a critical role in the formation and maintenance of tight junctions, which are essential for regulating the passage of molecules between cells. In CRC, claudin-1 is often overexpressed, leading to an increase in cell adhesion, which can contribute to the development and progression of the disease. Studies show that high levels of claudin-1 are associated with poor prognosis in CRC patients and targeting claudin-1 may have therapeutic potential for the treatment of CRC. Previously, we have identified a small molecule that inhibits claudin-1 dependent CRC progression. Reported herein are our lead optimization efforts around this scaffold to identify the key SAR components and the discovery of a key new compound that exhibits enhanced potency in SW620 cells.

From dopamine 4 to sigma 1: Synthesis, SAR and biological characterization of a piperidine scaffold of σ1 modulators.

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D4 and σ1 activity. In addition, we further profile lead compounds in a panel of off-target receptors, in vitro and in vivo pharmacokinetic studies. This has culminated in the discovery of multiple σ1 receptor modulators with properties that will allow for study in animal models.

Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists.

The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

Novel inhibitors of the renal inward rectifier potassium channel of the mosquito vector Aedes aegypti.

The mosquito continues to be the most lethal animal to humans due to the devastating diseases that it carries and transmits. Controlling mosquito-borne diseases relies heavily on vector management using neurotoxic insecticides with limited modes of action. This has led to the emergence of resistance to pyrethroids and other neurotoxic insecticides in mosquitoes, which has reduced the efficacy of chemical control agents. Moreover, many neurotoxic insecticides are not selective for mosquitoes and negatively impact beneficial insects such as honeybees. Developing new mosquitocides with novel mechanisms of action is a clear unmet medical need; this review covers the efforts made toward this end by targeting the renal inward rectifier potassium channel (Kir) of the mosquito.