RÉSUMÉ
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Sujet(s)
Intégrine alpha4bêta1/antagonistes et inhibiteurs , Intégrines/antagonistes et inhibiteurs , Administration par voie orale , Animaux , Aire sous la courbe , Polyarthrite rhumatoïde/induit chimiquement , Polyarthrite rhumatoïde/traitement médicamenteux , Maladie de Crohn/traitement médicamenteux , Modèles animaux de maladie humaine , Période , Humains , Intégrine alpha4bêta1/métabolisme , Intégrines/métabolisme , Cellules Jurkat , Microsomes du foie/métabolisme , RatsRÉSUMÉ
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Sujet(s)
Intégrine alpha4/composition chimique , Polyéthylène glycols/composition chimique , Animaux , Anticorps monoclonaux/composition chimique , Anticorps monoclonaux/immunologie , Anticorps monoclonaux/pharmacocinétique , Esters , Période , Humains , Injections sous-cutanées , Intégrine alpha4/immunologie , Intégrine alpha4/métabolisme , Cellules Jurkat , RatsRÉSUMÉ
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.
Sujet(s)
Antirhumatismaux/pharmacologie , Intégrine alpha4bêta1/antagonistes et inhibiteurs , Pyrimidines/pharmacologie , Sulfonamides/pharmacologie , Animaux , Antirhumatismaux/administration et posologie , Antirhumatismaux/synthèse chimique , Arthrite expérimentale/traitement médicamenteux , Asthme/traitement médicamenteux , Adhérence cellulaire/effets des médicaments et des substances chimiques , Collagène de type II/antagonistes et inhibiteurs , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Femelle , Fibronectines/composition chimique , Humains , Souris , Souris de lignée C57BL , Modèles moléculaires , Conformation moléculaire , Sclérose en plaques/traitement médicamenteux , Pyrimidines/administration et posologie , Pyrimidines/synthèse chimique , Rats , Rats de lignée LEW , Rat Sprague-Dawley , Relation structure-activité , Sulfonamides/administration et posologie , Sulfonamides/synthèse chimiqueRÉSUMÉ
A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.
Sujet(s)
Asthme/traitement médicamenteux , Modèles animaux de maladie humaine , Intégrine alpha4bêta1/antagonistes et inhibiteurs , Pyrimidines/usage thérapeutique , Administration par voie orale , Animaux , Asthme/métabolisme , Biodisponibilité , Découverte de médicament , Pyrimidines/pharmacocinétique , OvisRÉSUMÉ
INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.
RÉSUMÉ
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Sujet(s)
Maladie d'Alzheimer/traitement médicamenteux , Amyloid precursor protein secretases/antagonistes et inhibiteurs , Amyloid precursor protein secretases/métabolisme , Pyrazoles/pharmacologie , Sulfonamides/pharmacologie , Animaux , Cristallographie aux rayons X , Humains , Concentration inhibitrice 50 , Modèles moléculaires , Pyrazoles/composition chimique , Pyrazoles/pharmacocinétique , Rats , Rat Sprague-Dawley , Relation structure-activité , Sulfonamides/composition chimique , Sulfonamides/pharmacocinétiqueRÉSUMÉ
A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.