RÉSUMÉ
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metabolism, and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While preserving target potency, the novel fluoro-derivatives showed greatly improved permeability as well as enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure.
RÉSUMÉ
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.
Sujet(s)
Arthrite expérimentale/traitement médicamenteux , Mitogen-Activated Protein Kinase 14/antagonistes et inhibiteurs , Pyrazines/administration et posologie , Pyrazoles/administration et posologie , Pyridines/administration et posologie , Pyrimidines/administration et posologie , Administration par voie orale , Animaux , Modèles animaux de maladie humaine , Antienzymes/administration et posologie , Antienzymes/synthèse chimique , Antienzymes/composition chimique , Lipopolysaccharides/antagonistes et inhibiteurs , Lipopolysaccharides/pharmacologie , Souris , Structure moléculaire , Pyrazines/synthèse chimique , Pyrazines/composition chimique , Pyrazoles/synthèse chimique , Pyrazoles/composition chimique , Pyridines/synthèse chimique , Pyridines/composition chimique , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Rats , Relation structure-activité , Facteur de nécrose tumorale alpha/antagonistes et inhibiteurs , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
Sujet(s)
Antirhumatismaux/synthèse chimique , Pyridines/synthèse chimique , p38 Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Animaux , Antirhumatismaux/pharmacologie , Antirhumatismaux/usage thérapeutique , Arthrite expérimentale/induit chimiquement , Arthrite expérimentale/traitement médicamenteux , Collagène , Modèles animaux de maladie humaine , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Imidazoles/composition chimique , Lipopolysaccharides/pharmacologie , Souris , Oxazoles/composition chimique , Pyridines/pharmacologie , Pyridines/usage thérapeutique , Rats , Relation structure-activité , Thiazoles/composition chimique , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.