Bioorganic & medicinal chemistry letters
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Bioorg. Med. Chem. Lett. · Dec 2016
ReviewGPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space.
GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.
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Voltage-gated sodium channels (Navs) are an important family of transmembrane ion channel proteins and Nav drug discovery is an exciting field. Pharmaceutical investment in Navs for pain therapeutics has expanded exponentially due to genetic data such as SCN10A mutations and an improved ability to establish an effective screen sequence for example IonWorks Barracuda®, Synchropatch® and Qube®. Moreover, emerging clinical data (AZD-3161, XEN402, CNV1014802, PF-05089771, PF-04531083) combined with recent breakthroughs in Nav structural biology pave the way for a future of fruitful prospective Nav drug discovery.
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Bioorg. Med. Chem. Lett. · Jul 2014
ReviewRecent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus.
Despite the availability of established medication for treatment of type 2 diabetes mellitus (T2DM) there still remains a significant unmet need for new effective, oral antidiabetic agents that improve glycemic control while maintaining an excellent safety profile. In this regard the FFA1 receptor has emerged as an attractive target in recent years. Activation of the FFA1 receptor has been shown to not only amplify glucose induced insulin secretion from pancreatic beta cells but also to stimulate incretin secretion from intestinal endocrine cells. The current review highlights on the latest developments and clinical data from evolving research on the potential of FFA1 agonists as effective treatment for T2DM.