1377503-12-2Relevant articles and documents
Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)
Cheung, Atwood K.,Hurley, Brian,Kerrigan, Ryan,Shu, Lei,Chin, Donovan N.,Shen, Yiping,O'Brien, Gary,Sung, Moo Je,Hou, Ying,Axford, Jake,Cody, Emma,Sun, Robert,Fazal, Aleem,Fridrich, Cary,Sanchez, Carina C.,Tomlinson, Ronald C.,Jain, Monish,Deng, Lin,Hoffmaster, Keith,Song, Cheng,Van Hoosear, Mailin,Shin, Youngah,Servais, Rebecca,Towler, Christopher,Hild, Marc,Curtis, Daniel,Dietrich, William F.,Hamann, Lawrence G.,Briner, Karin,Chen, Karen S.,Kobayashi, Dione,Sivasankaran, Rajeev,Dales, Natalie A.
, p. 11021 - 11036 (2018)
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
Ir-Catalyzed ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions
Chattopadhyay, Buddhadeb,Dannatt, Jonathan E.,Andujar-De Sanctis, Ivonne L.,Gore, Kristin A.,Maleczka, Robert E.,Singleton, Daniel A.,Smith, Milton R.
supporting information, p. 7864 - 7871 (2017/06/20)
A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C-H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it. From further computational work a second generation, in silico designed catalyst emerged, where replacing Bpin with Beg (eg = ethylene glycolate) was predicted to significantly improve ortho selectivity. Experimentally, reactions employing B2eg2 gave ortho selectivities > 99%. Adding triethylamine significantly improved conversions. This ligand-substrate electrostatic interaction provides a unique control element for selective C-H functionalization.
INHIBITORS OF HIV REPLICATION
-
, (2012/06/01)
The present invention relates to novel 2,3,4-substituted 5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine compounds and pharmaceutically acceptable salts thereof, to compositions containing such compounds and to the use of such compounds as inhibitors of HIV replication.