37806-29-4Relevant articles and documents
Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold
Crowley, Vincent M.,Khandelwal, Anuj,Mishra, Sanket,Stothert, Andrew R.,Huard, Dustin J. E.,Zhao, Jinbo,Muth, Aaron,Duerfeldt, Adam S.,Kizziah, James L.,Lieberman, Raquel L.,Dickey, Chad A.,Blagg, Brian S. J.
, p. 3471 - 3488 (2016/05/19)
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.
Truncated (N)-methanocarba nucleosides as A1 adenosine receptor agonists and partial agonists: Overcoming lack of a recognition element
Tosh, Dilip K.,Phan, Khai,Deflorian, Francesca,Wei, Qiang,Gao, Zhan-Guo,Jacobson, Kenneth A.
supporting information; experimental part, p. 626 - 631 (2011/10/05)
A1 adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A1AR were truncated to eliminate 5′-CH 2OH. This modification previously converted A3AR agonists into antagonists, but the comparable effect at A1AR is unknown. In comparison to ribosides, affinity at the A1AR was less well preserved than that at the A3AR, although a few derivatives were moderately A1AR selective, notably full agonist 21 (N6- dicyclopropylmethyl, Ki 47.9 nM). Thus, at the A1AR, recognition elements for nucleoside binding depend more on 5′ region interactions, and in their absence, A3AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A1 but not A3AR. The derivatives ranged from partial to full agonists in A1AR-mediated adenylate cyclase inhibition. Truncated derivatives have more druglike physical properties than other A1AR agonists; this approach is appealing for preclinical development. This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.
Dynamic kinetic asymmetric synthesis of substituted pyrrolidines from racemic cyclopropanes and aldimines: Reaction development and mechanistic insights
Parsons, Andrew T.,Smith, Austin G.,Neel, Andrew J.,Johnson, Jeffrey S.
supporting information; experimental part, p. 9688 - 9692 (2010/09/06)
An enantioselective preparation of 2,5-cis-disubstituted pyrrolidines has been achieved via a dynamic kinetic asymmetric transformation (DyKAT) of racemic donor-acceptor cyclopropanes and (E)-aldimines. Mechanistic studies suggest that isomerization of the aldimine or resultant iminium to the Z geometry is not a pathway that furnishes the observed 2,5-cis-disubstituted products.
