184832-31-3Relevant academic research and scientific papers
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS
Hodges, Timothy R.,Abbott, Jason R.,Little, Andrew J.,Sarkar, Dhruba,Salovich, James M.,Howes, Jennifer E.,Akan, Denis T.,Sai, Jiqing,Arnold, Allison L.,Browning, Carrie,Burns, Michael C.,Sobolik, Tammy,Sun, Qi,Beesetty, Yugandhar,Coker, Jesse A.,Scharn, Dirk,Stadtmueller, Heinz,Rossanese, Olivia W.,Phan, Jason,Waterson, Alex G.,McConnell, Darryl B.,Fesik, Stephen W.
, p. 8875 - 8894 (2018)
Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ～30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation
Orjales, Aurelio,Mosquera, Ramón,Labeaga, Luis,Rodes, Rosa
, p. 586 - 593 (2007/10/03)
A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pK(i) = 9.2) exhibited higher affinity for the 5- HT3 receptor than did tropisetron and granisetron, while compound 7q (pK(i) = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pK(i) = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pK(i) = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
