We found that preventive chronic treatment with ARN16186 was efficacious in slowing disease progression and preserving locomotor activity in EAE mice. We assessed whether enzyme inhibition affected the severity of neurological symptoms and modulated immune cell infiltration into the central nervous system of EAE mice. To address this goal, we used ARN16186, a small molecule specifically designed and synthesized as a pharmacological tool to inhibit NAAA. Targeting these cell populations by inhibiting NAAA may be a promising pharmacological strategy to modulate the inflammatory aspect of MS and manage disease progression. N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a proinflammatory enzyme induced by phlogosis and overexpressed in macrophages and microglia of EAE mice. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.Įxperimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), in which myeloid cells sustain inflammation, take part in priming, differentiation, and reactivation of myelin-specific T-cells, and cause direct myelin damage. After an initial screening campaign, a careful structure–activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclooctane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50 = 0.042 μM) with a non-covalent mechanism of action. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclooctane structural core. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. Only application prototypes defined in different discovery rules can result in discovering the same application.Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In this situation only the first prototype discovery will succeed, the rest will report appropriate LLD error.
If an application is not discovered anymore all discovered items are automatically removed from it, even if the application itself is not yet removed because of the 'lost resources period' setting.Īpplication prototypes defined by one discovery rule can't discover the same application. Like other discovered entities applications follow the lifetime defined in discovery rule ('keep lost resources period' setting) - they are removed after not being discovered for the specified number of days. If created application prototype is not used by any item prototype it gets removed from 'Application prototypes' list automatically. One application prototype can be used by several item prototypes of the same discovery rule. Notes on low-level discovery Application discoveryĪpplication prototypes support LLD macros.
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