135391-08-1Relevant articles and documents
Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics
Falasca, Marco,Keating, Damien J.,Kizilkaya, Hüsün Sheyma,Kokh, Elena,Mancera, Ricardo L.,Massi, Massimiliano,Paternoster, Silvano,Rosenkilde, Mette Marie,Simpson, Peter V.
, (2021/08/30)
Metabolic diseases, such as obesity and type 2 diabetes, are relentlessly spreading worldwide. The beginning of the 21st century has seen the introduction of mechanistically novel types of drugs, aimed primarily at keeping these pathologies under control. In particular, an important family of therapeutics exploits the beneficial physiology of the gut-derived glucagon-like peptide-1 (GLP-1), with important clinical benefits, from glycaemic control to cardioprotection. Nonetheless, these protein-based drugs act systemically as exogenous GLP-1 mimetics and are not exempt from side effects. The food-derived lipid oleoyl-lysophosphatidylinositol (LPI) is a potent GPR119-dependent GLP-1 secreting agent. Here we present a structure-activity relationship (SAR) study of a synthetic library of oleoyl-LPI mimetics capable to induce the physiological release of GLP-1 from gastrointestinal enteroendocrine cells (EECs). The best lead compounds have shown potent and efficient release of GLP-1 in vitro from human and murine cells, and in vivo in diabetic db/db mice. We have also generated a molecular model of oleoyl-LPI, as well as its best performing analogues, interacting with the orthosteric site of GPR119, laying foundational evidence for their pharmacological activity.
A Convenient Protocol for the Synthesis of Fatty Acid Amides
Johansson, Silje J. R.,Johannessen, Tonje,Ellefsen, Christiane F.,Ristun, Mali S.,Antonsen, Simen,Hansen, Trond V.,Stenstrom, Yngve,Nolsoe, Jens M. J.
supporting information, p. 213 - 217 (2019/01/14)
Several classes of biologically occurring fatty acid amides have been reported from mammalian and plant sources. Many amides conjugated with fatty acids of mammalian origin exhibit specific activation of individual receptors. Their potential as pharmacological tools or as lead compounds towards the development of novel therapeutics is of great interest. Hence, access to such amides by a practical, high-yielding and scalable protocol without affecting the geometry or position of sensitive functionalities is needed. A protocol that meets all these requirements involves activation of the corresponding acid with carbonyl diimidazole (CDI) followed by reaction with the desired amine or its hydrochloride. More than fifty compounds have been prepared in generally high yields.
Analysis of chain length, substitution patterns, and unsaturation of AM-404 derivatives as 20S proteasome stimulators
Coleman, Rachel A.,Muli, Christine S.,Zhao, Yizhou,Bhardwaj, Atul,Newhouse, Timothy R.,Trader, Darci J.
supporting information, p. 420 - 423 (2019/01/04)
Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis-alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404.
