139194-80-2Relevant articles and documents
A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove
Bonnar, James,Dixon, Ian,Evison, Benny J.,Kelly, Graham E.,Kumar, Sanjay,Lambert, Gilles,Nativel, Brice,Palmer, James T.,Parmar, Jasneet,Rathi, Anuj Kumar,Suchowerska, Alexandra K.,Tang, Wei,Teng, Yanfen,Treutlein, Herbert,Wang, Jie,Xu, Yanfeng,Zeng, Jun,Zhu, Qing,Chemello, Kévin
supporting information, (2020/02/13)
Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 μM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 μM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.
Design, synthesis and structure–activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands
Szymańska, Ewa,Cha?upnik, Paulina,Szczepańska, Katarzyna,Cu?ado Moral, Ana Maria,Pickering, Darryl S.,Nielsen, Birgitte,Johansen, Tommy N.,Kie?-Kononowicz, Katarzyna
, p. 5568 - 5572 (2016/11/09)
A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1–GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Kivalues in the range of 4.9–7.5?μM). A structure–activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.
SULFONYL-SUBSTITUTED ARYL COMPOUNDS AS MODULATORS OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS
-
Page/Page column 34, (2008/06/13)
Compounds as modulators of peroxisome proliferator activated receptors, pharmaceutical compositions comprising the same, and methods of treating disease using the same are disclosed.
