Synthesis and anti‐diabetic activity of novel biphenylsulfonamides as glucagon receptor antagonists

Abstract

Type 2 diabetes is characterized by chronic hyperglycemia. Insulin, a hormone secreted from pancreatic β-cells, decreases blood glucose levels, and glucagon, a hormone secreted from pancreatic α-cells, increases blood glucose levels by counterregulation of insulin through stimulation of hepatic glucose production. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, inhibition of the glucagon receptor is one strategy for the treatment of hyperglycemia in type 2 diabetes. In this paper, we report a series of biphenylsulfonamide derivatives that were designed, synthesized, and then evaluated by cAMP and hepatic glucose production assays as glucagon receptor antagonists. Of these, compound 7aB-3 decreased glucagon-induced cAMP production and glucagon-induced glucose production in the in vitro assays. Glucagon challenge tests and glucose tolerance tests showed that compound 7aB-3 significantly inhibited glucagon-induced glucose increases and improved glucose tolerance. These results suggest that compound 7aB-3 has therapeutic potential for the treatment of type 2 diabetes.

Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia

“…Nonetheless, the idea that blocking glucagon action could be an additional therapy for diabetes has sparked interest in the development of potential pharmacological interventions that target the hepatic glucagon receptor. Blocking glucagon action can be achieved through: i) glucagon receptor antagonists, in particular small molecule antagonists, which can allosterically or competitively inhibit glucagon action (9)(10)(11); ii) glucagon receptor neutralizing antibodies (12); and iii) antisense oligonucleotides against the glucagon receptor (13). However, blockade of the glucagon receptor may induce a-cell hyperplasia and exacerbate hyperaminoacidemia (14)(15)(16) through impairments in a liver-alpha cell axis [reviewed in (17)], and increased risk of hyperlipidemia (18).…”

Synthesis and SAR investigation of biphenylaminoquinoline derivatives with benzyloxy substituents as promising anticancer agents

“…Their inherent lipophilicity and rigidity render biphenyls highly favorable for druglike properties, leading to their prevalent use in the synthesis of various chemical compounds (Bordi et al, 2012;Ghosh et al, 2015;Kotian et al, 2009). Moreover, biphenyls exhibit a diverse range of pharmacological activities, including anticancer (Diao et al, 2019;Yang et al, 2020;Zeng et al, 2023), antimicrobial (Gao et al, 2021;Wang et al, 2022), antihypertensive (Liu et al, 2013), anti-inflammatory (Kuo et al, 2013;Lin et al, 2010), anti-diabetic (Lee et al, 2021;Thareja et al, 2023), antipsychotic (Bhosale et al, 2014), anti-HIV (Jin et al, 2022;Sang et al, 2019), and the treatment of neuropathic pain (Kim et al, 2016;Oka et al, 2018). Herein, we aim to offer a concise overview with a specific emphasis on the anticancer activity of biphenyls derivatives in recent publications.…”

Synthesis, crystal structure, DFT/HF, Hirshfeld surface, and molecular docking analysis of 4-(tert-butyl)-4-nitro-1,1-biphenyl

“…It serves as a central building block for basic liquid crystal and fluorescent layers in OLEDs [3,4]. The ability of biphenyls to undergo chemical changes to form substituted biphenyls has many biological and pharmaceutical applications, including anti-inflammatory, antimicrobial, antifungal, antidiabetic, anti-tumor, and anticancer properties [5][6][7][8][9]. The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists, in view of the fact that the new compounds synthesized by various standard methods should be safe, effective, and have fewer side effects.…”