RESUMO
TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.
Assuntos
Citocinas/imunologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/imunologia , TYK2 Quinase/imunologia , TYK2 Quinase/metabolismo , Animais , Citocinas/metabolismo , Humanos , Immunoblotting , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).
Assuntos
Janus Quinase 1/antagonistas & inibidores , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Cinética , Modelos Moleculares , Piridinas/química , Pirróis/química , Pirróis/farmacologia , RatosRESUMO
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
Assuntos
Antirreumáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Pirróis/síntese química , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Colágeno , Cristalografia por Raios X , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Janus Quinase 1/química , Janus Quinase 2/química , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , EstereoisomerismoRESUMO
Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
Assuntos
Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Imidazóis/química , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Piridinas/administração & dosagem , Piridinas/química , Pirróis/administração & dosagem , Pirróis/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
Assuntos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Animais , Bioensaio , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Hepatócitos/citologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Janus Quinase 1/química , Janus Quinase 2/química , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
Assuntos
Imidazóis/química , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Especificidade por SubstratoRESUMO
1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK(1) receptor antagonists. Substitution at the 6-exo-position led to high affinity NK(1) antagonists with a prolonged duration of action in vivo. Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel.
Assuntos
Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Animais , Células CHO , Cricetinae , Ciclização , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HumanosRESUMO
A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel.
Assuntos
Compostos Aza/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antagonistas dos Receptores de Neurocinina-1 , Compostos Aza/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Humanos , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 5-HT(7) receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.
Assuntos
Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Sulfonas/química , Sulfonas/metabolismo , Alquilação , Aminação , Ciclização , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist.
Assuntos
Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Tiazóis/síntese química , Tiazóis/farmacologia , Células Cultivadas , Humanos , Ligantes , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.
Assuntos
Amidinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Amidinas/metabolismo , Benzamidinas/síntese química , Benzamidinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Naftalenos/síntese química , Naftalenos/metabolismo , Ligação Proteica , Ensaio Radioligante , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.