RESUMO
It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound in plasma (fup) and measured CLint in buffer.
Assuntos
Microssomos Hepáticos , Modelos Biológicos , Animais , Ratos , Microssomos Hepáticos/metabolismo , Taxa de Depuração Metabólica , Fígado/metabolismo , Hepatócitos/metabolismo , Proteínas Sanguíneas/metabolismoRESUMO
Assessing whether compounds penetrate the brain can become critical in drug discovery, either to prevent adverse events or to reach the biological target. Generally, pre-clinical in vivo studies measuring the ratio of brain and blood concentrations (Kp) are required to estimate the brain penetration potential of a new drug entity. In this work, we developed machine learning models to predict in vivo compound brain penetration (as LogKp) from chemical structure. Our results show the benefit of including in vitro experimental data as auxiliary tasks in multi-task graph neural network (MT-GNN) models. MT-GNNs outperformed single-task (ST) models solely trained on in vivo brain penetration data. The best-performing MT-GNN regression model achieved a coefficient of determination of 0.42 and a mean absolute error of 0.39 (2.5-fold) on a prospective validation set and outperformed all tested ST models. To facilitate decision-making, compounds were classified into brain-penetrant or non-penetrant, achieving a Matthew's correlation coefficient of 0.66. Taken together, our findings indicate that the inclusion of in vitro assay data as MT-GNN auxiliary tasks improves in vivo brain penetration predictions and prospective compound prioritization.
Assuntos
Aprendizado de Máquina , Redes Neurais de Computação , Encéfalo , Descoberta de DrogasRESUMO
The discovery of novel imaging agents for positron emission tomography (PET) relies on medicinal chemistry best practices, including a good understanding of molecular and pharmacological properties required for the acquisition of relevant, high-quality images. This short note reviews the characteristics of a series of clinically successful imaging agents, providing guidance for the optimization of such molecular tools. PET imaging plays an important role in staging disease and in helping clinical dose selection, which is critical for the efficient development of drug candidates.
Assuntos
Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Compostos Radiofarmacêuticos/química , Tomografia por Emissão de Pósitrons/métodos , Sistema Nervoso CentralRESUMO
1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice. 2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100 mg/kg ABT inhibited the oral absorption of NVS-CRF38, Tmax was 4 hours for ABT-treated mice compared to 0.5 hours in the control group. 3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1 month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control). 4. Tmax values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function. 5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Triazóis/farmacologia , Administração Oral , Animais , Camundongos , Oxazóis/metabolismo , Pirazóis/metabolismoRESUMO
A cyclisation within a 4',5-bisthiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors led to a novel 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole tricyclic sub-series. The synthesis and optimisation of this 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole sub-series and the expansion to a related tricyclic 4,5-dihydrothiazolo[4,5-h]quinazoline sub-series are described. From this work analogues including 11, 12, 19 and 23 were identified as potent and selective PI3Kα inhibitor in vivo tool compounds.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Células CACO-2 , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Camundongos Nus , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
Here we describe the identification, structure-activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson's disease and Fragile X syndrome in proof of principle clinical studies.
Assuntos
Indóis/química , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Discinesia Induzida por Medicamentos/tratamento farmacológico , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Hipertermia Induzida , Indóis/farmacocinética , Indóis/farmacologia , Indóis/uso terapêutico , Levodopa/toxicidade , Masculino , Camundongos , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
Imaging agents for positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) have shown their utility in many situations, answering clinical questions related to drug development and medical considerations. The discovery and development of imaging agents follow a well-understood process, with variations related to available starting points and to the envisaged imaging application. This article describes the general development path leading from the expression of an imaging need and project initiation to a clinically usable imaging agent. The definition of the project rationale, the design and optimization of early leads, and the assessment of the imaging potential of an imaging agent candidate are followed by preclinical and clinical development activities that differ from those required for therapeutic agents. These include radiolabeling with a positron emitter and first-in-human clinical studies, to rapidly evaluate the ability of a new imaging agent to address the questions it was designed to answer.
Assuntos
Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Peso Molecular , AnimaisRESUMO
NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1ß and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1ß release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile.
Assuntos
Diabetes Mellitus Tipo 2 , Gota , Camundongos , Animais , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Interleucina-1beta/metabolismo , Caspase 1/metabolismoRESUMO
Peripheral immune cells and brain microglia exhibit an activated phenotype in premanifest Huntington's disease (HD) patients that persists chronically and correlates with clinical measures of neurodegeneration. However, whether activation of the immune system contributes to neurodegeneration in HD, or is a consequence thereof, remains unclear. Signaling through cannabinoid receptor 2 (CB(2)) dampens immune activation. Here, we show that the genetic deletion of CB(2) receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB(2) receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB(2) receptor antagonist blocks these effects. CB(2) receptors regulate blood interleukin-6 (IL-6) levels, and IL-6 neutralizing antibodies partially rescue motor deficits and weight loss in HD mice. These findings support a causal link between CB(2) receptor signaling in peripheral immune cells and the onset and severity of neurodegeneration in HD, and they provide a novel therapeutic approach to treat HD.
Assuntos
Doença de Huntington/imunologia , Doença de Huntington/metabolismo , Leucócitos/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Doença de Huntington/patologia , Interleucina-6/imunologia , Interleucina-6/metabolismo , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB2 de Canabinoide/imunologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aß following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.
Assuntos
Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/química , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Descoberta de Drogas , Etanolaminas/farmacologia , Sulfóxidos/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/sangue , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Química Encefálica , Cristalografia por Raios X , Ciclização , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Etanolaminas/química , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfóxidos/químicaRESUMO
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice.
Assuntos
Encéfalo/metabolismo , Indóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Indóis/metabolismo , Indóis/farmacocinética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Camundongos , Mutação , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.
Assuntos
Amidas/química , Amidas/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Pirróis/química , Pirróis/farmacologia , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , SolubilidadeRESUMO
A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.
Assuntos
Anticonvulsivantes/farmacologia , Quinazolinonas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Convulsões/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.
Assuntos
Antineoplásicos , Fosfatidilinositol 3-Quinases , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Compostos Orgânicos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzilaminas/química , Benzilaminas/farmacologia , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Benzilaminas/síntese química , Cristalografia por Raios X , Óxidos S-Cíclicos/síntese química , Ciclização , Inibidores Enzimáticos/síntese química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.
Assuntos
Amidas/química , Aminopiridinas/química , Ansiolíticos/química , Peptídeos/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzamidas/química , Encéfalo/metabolismo , Lactamas/química , Compostos Macrocíclicos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Humanos , Lactamas/síntese química , Lactamas/farmacologia , Compostos Macrocíclicos/farmacologia , Camundongos , Camundongos Transgênicos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Fragmentos de Peptídeos/química , Inibidores de Proteases/química , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Estrutura Secundária de Proteína/fisiologiaRESUMO
ABSTRACT: Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include N-methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism.
RESUMO
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). While multiple effective immunomodulatory therapies for MS exist today, they lack the scope of promoting CNS repair, in particular remyelination. Microglia play a pivotal role in regulating myelination processes, and the colony-stimulating factor 1 (CSF-1) pathway is a key regulator for microglia differentiation and survival. Here, we investigated the effects of the CSF-1 receptor kinase inhibitor, BLZ945, on central myelination processes in the 5-week murine cuprizone model by non-invasive and longitudinal magnetic resonance imaging (MRI) and histology. Therapeutic 2-week BLZ945 treatment caused a brain region-specific enhancement of remyelination in the striatum/cortex, which was absent in the corpus callosum/external capsule. This beneficial effect correlated positively with microglia reduction, increased oligodendrocytes and astrogliosis. Prophylactic BLZ945 treatment prevented excessive demyelination in the corpus callosum by reducing microglia and increasing oligondendrocytes. In the external capsule oligodendrocytes were depleted but not microglia and a buildup of myelin debris and axonal damage was observed. A similar microglial dysfunction in the external capsule with an increase of myelin debris was obvious in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice treated with cuprizone. Finally, therapeutic BLZ945 treatment did not change the disease course in experimental autoimmune encephalomyelitis mice, a peripherally driven neuroinflammation model. Taken together, our data suggest that a short-term therapeutic inhibition of the CSF-1 receptor pathway by BLZ945 in the murine cuprizone model enhances central remyelination by modulating neuroinflammation. Thus, microglia-modulating therapies could be considered clinically for promoting myelination in combination with standard-of-care treatments in MS patients.