High concentration electrophysiology-based fragment screen: Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

Wolkenberg, S. E.; Zhao, Zhijian; Mulhearn, James; Harrison, Scott T.; Sanders, John M.; Cato, Matthew J.; Jovanovska, Aneta; Panigel, Jacqueline; Cook, Sean P.; Henze, Darrell A.; Kane, Stefanie A.; Hartman, George D.; Barrow, James C.

doi:10.1016/j.bmcl.2010.12.115

Cited by 19 publications

(20 citation statements)

References 12 publications

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“…Nafomastat, a clinically used serine protease inhibitor (Fujii and Hitomi, 1981), inhibits ASIC currents, including the sustained component of the ASIC3 current, with an IC 50 of ;2-70 mM (Ugawa et al, 2007). More recently, the screening of a fragment library and subsequent optimization yielded 2-aminopyridine derivatives inhibiting ASIC3, with an IC 50 of ;3 mM (Wolkenberg et al, 2011). ASIC currents are inhibited by the local anesthetics tetracaine and lidocaine with IC 50 values of ;10 mM and by the K + channel inhibitor 4-aminopyridine with IC 50 values $1 mM (Lin et al, 2011;Boiko et al, 2013;Leng et al, 2013).…”

Section: Pharmacologymentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

2014

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Section: Pharmacologymentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

2014

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“…One example of this involved screening $1,300 fragments against the acid-sensing ion channel 3 in electrophysiology-based assays, yielding 32 hits in 12 separate chemical series. Parallel chemistry was used to make several hundred compounds, ultimately improving activity by a factor of 200 (Wolkenberg et al, 2011). In another case, a small fragment with very weak antibacterial activity was advanced using a combination of SAR-by-catalog and assay-driven chemistry to a potent molecule with in vivo efficacy against Staphylococcus aureus (Czaplewski et al, 2009).…”

Section: Chemical Approachesmentioning

confidence: 99%

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Erlanson

Davis

Jahnke

2019

Cell Chemical Biology

102

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Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization. Essentially, all models are wrong, but some are useful.

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“…Several antiprotozoal diarylamidines inhibit ASICs with IC 50 values of 0.3–38 μM (Chen et al , ). A recent screening of a fragment library followed by optimization led to ASIC3‐inhibiting 2‐aminopyridine derivatives with an IC 50 of ~3 μM (Wolkenberg et al , ).…”

Section: Acid‐sensing Ion Channelsmentioning

confidence: 99%

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19

Boscardin

Alijevic

Hummler

et al. 2016

British J Pharmacology

127

122

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*These authors contributed equally.Acid-sensing ion channels (ASICs) and the epithelial Na + channel (ENaC) are both members of the ENaC/degenerin family of amiloride-sensitive Na + channels. ASICs act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. ENaC mediates Na + reabsorption across epithelia of the distal kidney and colon and of the airways. ENaC is a clinically used drug target in the context of hypertension and cystic fibrosis, while ASIC is an interesting potential target. Following a brief introduction, here we will review selected aspects of ASIC and ENaC function. We discuss the origin and nature of pH changes in the brain and the involvement of ASICs in synaptic signalling. We expose how in the peripheral nervous system, ASICs cover together with other ion channels a wide pH range as proton sensors. We introduce the mechanisms of aldosterone-dependent ENaC regulation and the evidence for an aldosterone-independent control of ENaC activity, such as regulation by dietary K + . We then provide an overview of the regulation of ENaC by proteases, a topic of increasing interest over the past few years. In spite of the profound differences in the physiological and pathological roles of ASICs and ENaC, these channels share many basic functional and structural properties. It is likely that further research will identify physiological contexts in which ASICs and ENaC have similar or overlapping roles. AbbreviationsAQP, aquaporin; ASDN, aldosterone-sensitive distal nephron; ASIC, acid-sensing ion channel; BASIC, bile acid-activated ion channel; BK, big calcium-activated K + channel; CA, carbonic anhydrase; CAP-1, -2, or-3, channel activating proteases; Ca v , voltage-gated Ca2 + channel; CCD, cortical collecting duct; CD, collecting duct; PHA-1, pseudohypoaldosteronism type 1; CFTR, cystic fibrosis transmembrane conductance regulator; CNT, connecting tubule; CF, cystic fibrosis; CLCN/Kb, voltage-sensitive chloride channel Kb; DCT, distal convoluted tubule; DRG, dorsal root ganglion; ENaC, amiloride-sensitive epithelial sodium channel; EPSP, excitatory post-synaptic potential; FaNaC, FMRFa-activated Na + channel; FMRFa, PheMet-Arg-Phe-amide; GMQ, 2-guanidine-4-methylquinazoline; GPI, glycosylphosphatidyl-inositol; HAI, hepatocyte growth factor activator inhibitor; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; I A , A-type current of rapid inactivating K + channels; iGluR, ionotropic glutamate receptor; I K , K + current; I Na , Na + current; I h , current produced by HCN channels; I max , maximal current amplitude; Kir, inward rectifier K + channel; K v , voltage-gated K + channel; MR, mineralocorticoid receptor; Na v , voltage-gated Na + channel; NBC, Na + , -HCO 3 -cotransporter; NCC, Na +-Cl À cotransporter; NHE, Na +-H + exchanger; OSR1/SPAK, Ste20-related protein kinases; P2X, purinergic receptor; PcTx1, Psalmotoxin 1; pH 50 , pH of half-maximal activation; pHe, extracellular pH; pH 50 Inh./Act., pH of h...

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High concentration electrophysiology-based fragment screen: Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

Cited by 19 publications

References 12 publications

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19

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High concentration electrophysiology-based fragment screen: Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

Cited by 19 publications

References 12 publications

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na+ channel (ENaC): IUPHAR Review 19

Contact Info

Product

Resources

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International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19