Current Topics in Medicinal Chemistry - Volume 19, Issue 24, 2019

Diabetes is a global public health concern nowadays. The majority of diabetes mellitus (DM) patients belong to type 2 diabetes mellitus (T2DM), which is highly associated with obesity. The general principle of current therapeutic strategies for patients with T2DM mainly focuses on restoring cellular insulin response by potentiating the insulin-induced signaling pathway. In late-stage T2DM, impaired insulin production requires the patients to receive insulin replacement therapy for maintaining their glucose homeostasis. T2DM patients also demonstrate a drop of brain-derived neurotrophic factor (BDNF) in their circulation, which suggests that replenishing BDNF or enhancing its downstream signaling pathway may be beneficial. Because of their protein nature, recombinant insulin or BDNF possess several limitations that hinder their clinical application in T2DM treatment. Thus, developing orally active “insulin pill” or “BDNF pill” is essential to provide a more convenient and effective therapy. This article reviews the current development of non-peptidyl chemicals that mimic insulin or BDNF and their potential as anti-diabetic agents.

Recent regulatory approval of several immune checkpoint inhibitors has ushered in a new era of cancer immunotherapies with the promise of achieving a durable response. This represents a paradigm shift in cancer treatment from directly targeting tumor cells to harnessing the power of a patient’s own immune system to destroy them. The cGAS-STING pathway is the major cytosolic dsDNA sensing pathway that plays a pivotal role in the innate antitumor immune response. With a fundamentally different mode of action (MOA) than immune checkpoint modulators, STING activation can potentially enhance tumor immunogenicity and improve patient responses as a single agent or by synergizing with existing anti-cancer drugs. Therefore, there has been intense interest from the pharmaceutical industry and academic institutions in the search for potent STING agonists as immunotherapies in oncology. In this article, we review briefly the cGAS-STING pathway and STING agonists that are in the clinical and preclinical studies, summarize recently disclosed patent applications and published journal articles in the field and cover both cyclic dinucleotide (CDN) analogs and non-nucleic acid derived STING agonists.

Toll-like receptors (TLRs) 7 and 8 play an important role in the activation of innate immune cells in mammals. These evolutionarily conserved receptors serve as important sentinels in response to infection. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response. The emergence of new structural and small molecule information generated in the last decade has contributed enormously to our understanding of this highly sophisticated process of innate immunity signaling. This review will focus on recent developments in the small molecule activation of TLR 7 and 8.

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

Transient receptor potential vanilloid (TRPV) 4 belongs to the TRPV subfamily of TRP ion channels. TRPV4 channels play a critical role in chondrocytes and thus TRPV4 is an attractive target of Disease-Modifying Osteoarthritis Drugs (DMOADs). Initial investigations of small molecules by Glaxo Smith Klein (GSK) as both agonists and antagonists via oral/intravenous administration have led to the use of existing agonists as lead compounds for biological studies. Our recent results suggest that local injection of a TRPV4 agonist is a potential treatment for osteoarthritis (OA). This review briefly summarizes updates regarding TRPV4 agonists based on recent advances in drug discovery, and particularly the local administration of TRPV4 agonists.