Delving into the Latest Updates on S-38093 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

H3 receptor

Mechanism

H3 receptor antagonists(Histamine H3 receptor antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Alzheimer Disease

Originator Organization

Les Laboratoires Servier SAS

Active Organization-

Inactive Organization

Les Laboratoires Servier SAS

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC17H25ClN2O2

InChIKeyAFSVOZDCVFYWFG-UHFFFAOYSA-N

CAS Registry1222097-72-4

View All Structures (2)

This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2–3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer’s disease. The object recognition task allows the study of natural forgetting and is classically used in assessing drug effects on memory. Here, we show that mice exhibit significant object recognition at short (15 min) but not long (24 h) retention intervals separating the familiarization and recognition phases. S 47445 (1.0, 3.0, and 10.0 mg/kg) and S 38093 (0.3, 1.0, and 3.0 mg/kg), both administered postoperatively, 1 h before familiarization and recognition sessions, rescued memory at the long retention interval; their memory-enhancing effects were as powerful as those obtained with donepezil or memantine (1.0 and 3.0 mg/kg for both compounds). Thus, S 38093 and S 47445, detected as positive controls in the object recognition task, are promising compounds for the treatment of amnesic syndromes.

01 Jan 2018·European Journal of PainQ2 · MEDICINE

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats

Q2 · MEDICINE

Article

Author: Bravo, L. ; Mico, J.A. ; Marchand, F. ; Chaumette, T. ; Eschalier, A. ; Llorca‐Torralba, M. ; Sors, A. ; Berrocoso, E. ; Ardid, D. ; Chalus, M. ; Chapuy, E.

AbstractBackgroundHistamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists.MethodsThe antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin.ResultsWhile S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin‐induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw‐pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin‐induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus.ConclusionsThese results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent‐induced neuropathic pain.SignificanceS 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin‐induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.

01 May 2017·European Journal of PharmacologyQ3 · MEDICINE

Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors

Q3 · MEDICINE

Article

Author: Arrang, Jean-Michel ; Panayi, Fany ; Lestage, Pierre ; Bert, Lionel ; Chollet, Anne-Marie ; Audinot, Valérie ; Delbos, Jean-Marie ; Kontkanen, Outi ; Huhtala, Tuulia ; Sors, Aurore ; Casara, Patrick ; Nosjean, Olivier ; Buisson, Bruno ; Favale, Dominique ; Steidl, Esther

Histaminergic H3 inverse agonists, by stimulating central histamine release, represent attractive drug candidates to treat cognitive disorders. The present studies aimed to describe the mechanistic profile of S 38093 a novel H3 receptors inverse agonist. S 38093 displays a moderate affinity for rat, mouse and human H3 receptors (Ki=8.8, 1.44 and 1.2µM, respectively) with no affinity for other histaminergic receptors. In cellular models, the compound was able to antagonize mice H3 receptors (K_B=0.65µM) and to suppress cAMP decrease induced by an H3 agonist via human H3 receptors (K_B=0.11µM). The antagonism properties of the compound were confirmed by electrophysiological studies on rat hippocampal slices (from 0.1μM). In cells expressing a high H3 density, S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC₅₀=9 and 1.7µM, respectively). S 38093 was rapidly absorbed in mouse and rat (T_max=0.25-0.5h), slowly in monkey (2h), with a bioavailability ranging from 20% to 60% and t_1/2 ranging from 1.5 to 7.4h. The compound was widely distributed with a moderate volume of distribution and low protein binding. The brain distribution of S 38093 was rapid and high. In mice, S 38093 significantly increased ex vivo N-tele-Methylhistamine cerebral levels from 3mg/kg p.o. and antagonized R-α-Methylhistamine-induced dipsogenia from 10mg/kg i.p. Taken together, these data suggest that S 38093, a novel H3 inverse agonist, is a good candidate for further in vivo evaluations, in particular in animal models of cognition.

100 Deals associated with S-38093

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	IT	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	DE	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	HU	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	PT	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	PL	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	CL	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	ES	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	MX	Les Laboratoires Servier SAS	-
Alzheimer Disease	Phase 2	SK	Les Laboratoires Servier SAS	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


CTAD2015	Phase 2	-	711	S 38093 2mg	pccuyfjkup(zwhtljyrib) = No significant difference in change from baseline was demonstrated on function (DAD) czdrlcqztx (pxilnrryzj ) View more	Negative	04 Nov 2015
				S 38093 5mg
AAIC2009	Not Applicable	Cognitive Dysfunction	5	S 38093 0.10mg/kg	utxluzumif(tpbepxrdbq) = ykjpqucfai itvjmsqefa (zdrbpnlmjt )	Positive	01 Jul 2009
				S 38093 0.30mg/kg	utxluzumif(tpbepxrdbq) = vktowexbbb itvjmsqefa (zdrbpnlmjt )