RÉSUMÉ
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
Sujet(s)
Chimie pharmaceutique/méthodes , Intestins/effets des médicaments et des substances chimiques , Récepteurs à activité tyrosine kinase/antagonistes et inhibiteurs , Absorption , Adénosine triphosphate/composition chimique , Administration par voie orale , Animaux , Sites de fixation , Biodisponibilité , Cristallographie aux rayons X/méthodes , Conception de médicament , Humains , Concentration inhibitrice 50 , Modèles chimiques , Agrégation plaquettaire , Rats , Récepteurs à activité tyrosine kinase/composition chimiqueRÉSUMÉ
We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.
Sujet(s)
Benzoxazines/composition chimique , Benzoxazines/pharmacologie , Conception de médicament , Pyridines/composition chimique , Rénine/antagonistes et inhibiteurs , Amination , Animaux , Benzoxazines/synthèse chimique , Benzoxazines/métabolisme , Cristallographie aux rayons X , Mâle , Modèles moléculaires , Structure moléculaire , Rats , Rat Sprague-Dawley , Rénine/composition chimique , Rénine/métabolisme , Relation structure-activitéRÉSUMÉ
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Sujet(s)
Chimie pharmaceutique/méthodes , Pyrimidines/composition chimique , Rénine/antagonistes et inhibiteurs , Animaux , Cristallographie aux rayons X , Conception de médicament , Concentration inhibitrice 50 , Modèles chimiques , Modèles moléculaires , Conformation moléculaire , Pyrimidines/synthèse chimique , Pyrimidines/pharmacologie , Rats , Rat Sprague-Dawley , Relation structure-activitéRÉSUMÉ
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.