SL-05. Ion Channel Modulators. Nav1.8

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SL-05. Ion Channel Modulators. Nav1.8 The blockage of voltage-gated sodium channels may hydrophobic regions and a basic nitrogen (i.e. lidocaine and effectively control such pathological conditions as chronic amitriptyline). To exploit this pharmacophore model, a pain, epilepsy, and different arrhythmias. Those located in library of structurally novel biaryl ethers was created and nervous system tetrodotoxin-resistant Nav1.8 and tested in vitro in the human Nav1.8/β3 sodium channel cell tetrodotoxin-sensitive Nav1.7 are known to be critical for the line. Some compounds demonstrated activity at Nav1.8 sensation of pain and have a relatively small number of side channel comparable with the activity of amitriptyline – a effects [1] nonspecific modulator of Na and K ion channels. The analysis of several well-known ion-channel blockers revealed common pharmacophoric features: two F F N N O O O Cl O O O Cl F N Lidocaine Amitriptyline Signature Library 05 Formats Supplementary Information 80 compounds per plate Nav1.8 Inhibition% TP1/TP2 @1 μM 0.1 mg; 1 mg; 2 mg dry film/powder Solubility data in PBS 0.1 µmol; 1 µmol DMSO solutions SL#5_ICh_04-16.sdf References: 1. ChemMedChem Special Issue: Ion Channel Drug Discovery Volume 7, Issue 10, pages 1712–1740 doi: 10.1002/cmdc.201200298. Contact us: USA: +1 336 721 1617 [email protected] Japan: +81-80-3401-9097 [email protected] Europe/Global: [email protected] SL-51. Nav1.8 Channel Modulators Voltage-gated sodium channels are involved in has been used to carry out an exhaustive search on a 20K+ signal transduction in electrically excitable tissues such as set of natural product-like compounds. The highest scoring those found in muscles, the heart, and nerves. Deregulated compounds were screened in vitro in the human Nav1.8/β3 function of voltage-gated sodium channels is observed in sodium channel cell line. The Nav1.8 blocking effects were various pathological and disease conditions including pain, evaluated using the IonWorksTM Barracuda system. Blockage CNS, and cardiac disorders. Specific channel isoforms, NaV1.7, of the sodium channel was performed at 1 µM of a tested NaV1.8 and NaV1.9 are predominantly expressed in sensory compound using a stimulus voltage pattern measuring peak neurons thus providing a strong rationale as anti-pain targets current amplitudes for two test pulses TP1 (tonic inhibition) [1]. and TP2 (inactivated state inhibition). Based on the analysis of several known NaV1.8- blockers we have developed a pharmacophore model which N H F N N F N N N N F F N N N Cl O H O N O N O O N O N O N H N N O N N N S Cl O N F O Signature Library 51 Formats Supplementary Information 80 compounds per plate SL#51_SL#51_Nav18_ICh.sdf 0.1 mg; 1 mg; 2 mg dry film/powder Supplementary Information 0.1 µmol; 1 µmol DMSO solutions Tonic block of Nav1.8 , at 1.0 µM – TP1 Inactivated state inhibition of Nav1.8 at 1.0 µM – TP2 References: 1. Channels (Austin). 2015 Nov-Dec; 9(6): 360–366; doi: 10.1080/19336950.2015.1079674 Contact us: USA: +1 336 721 1617 [email protected] Japan: +81-80-3401-9097 [email protected] Europe/Global: [email protected] .

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