Salovich J.M.,Vanderbilt Program in Drug Discovery |
Salovich J.M.,Vanderbilt Specialized Chemistry Center for Accelerated Probe Development |
Lindsley C.W.,Vanderbilt Program in Drug Discovery |
Lindsley C.W.,Vanderbilt Specialized Chemistry Center for Accelerated Probe Development |
And 3 more authors.
Tetrahedron Letters | Year: 2010
Herein we report a general synthesis of 1,3-diarylsubstituted indazoles utilizing a two-step Suzuki crosscoupling/deprotection/N-arylation sequence. This procedure proceeds in excellent overall yield starting from the 3-iodo-N-Boc indazole derivative allowing for rapid access to these compounds. © 2010 Published by Elsevier Ltd. All rights reserved.
Miller M.,Johns Hopkins University |
Shi J.,Johns Hopkins University |
Zhu Y.,University of Texas Health Science Center at Houston |
Kustov M.,Queens University of Belfast |
And 17 more authors.
Journal of Biological Chemistry | Year: 2011
Transient receptor potential canonical (TRPC) channels are Ca 2+-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca 2+ rise in response to stimulation of mouse TRPC4β by μ-opioid receptors. ML204 inhibited TRPC4β-mediated intracellular Ca 2+ rise with an IC 50 value of 0.96 μM and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4β currents activated through either μ-opioid receptor stimulation or intracellular dialysis of guanosine 5′-3-O-(thio)triphos-phate (GTPγS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 μM ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPγS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Raphemot R.,Vanderbilt University |
Lonergan D.F.,Vanderbilt University |
Nguyen T.T.,Vanderbilt University |
Utley T.,Vanderbilt University |
And 9 more authors.
Frontiers in Pharmacology | Year: 2011
The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions.The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure-activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure-function relationships of these Kir channels. © 2011 Raphemot, Lonergan, Nguyen, Utley, Lewis, Kadakia, Weaver, Gogliotti, Hopkins, Lindsley and Denton.
Cheung Y.-Y.,Vanderbilt University |
Cheung Y.-Y.,Vanderbilt Specialized Chemistry Center for Accelerated Probe Development |
Zamorano R.,Vanderbilt University |
Blobaum A.L.,Vanderbilt University |
And 7 more authors.
ACS Combinatorial Science | Year: 2011
Using a functional high-throughput screening (HTS) and subsequent solution-phase parallel synthesis approach, we have discovered a novel series of positive allosteric modulators formGlu 4, a G-protein coupled receptor. This series is comprised of a homopiperazine central core. The solution-phase parallel synthesis and SAR of analogs derived from this series will be presented. This series of positive allosteric modulators of mGlu4 provide critical research tools to further probe the mGlu 4-mediated effects in Parkinson's disease. © 2011 American Chemical Society.
Robichaud A.J.,Lundbeck |
Engers D.W.,Vanderbilt University |
Engers D.W.,Vanderbilt Specialized Chemistry Center for Accelerated Probe Development |
Lindsley C.W.,Vanderbilt University |
And 3 more authors.
ACS Chemical Neuroscience | Year: 2011
This Review describes recent activity in the advancement of ligands for the metabotropic glutamate 4 receptor subtype and their potential utility as central nervous system (CNS) therapeutics. Until recently, there was a paucity of compounds with suitable selectivity and druglike properties to elucidate the value of this target. The search for selective entities has led several groups to the investigation of allosteric modulators as a path to optimization of potential ligands. Recent efforts, discussed here, have afforded a variety of derivatives with improvements in potency, solubility, and pharmacokinetic properties that garner support for continued investigation and optimization. © 2011 American Chemical Society.