RÉSUMÉ
Attempts to lock the active conformation of compound 4, a PI3Kß/δ inhibitor (PI3Kß cell IC50 0.015µM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kß/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kß cell IC50 0.0011µM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014µM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kß/δ preclinical candidates.
Sujet(s)
Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Benzopyranes/composition chimique , Benzopyranes/usage thérapeutique , Phosphohydrolase PTEN/génétique , Inhibiteurs des phosphoinositide-3 kinases , Tumeurs de la prostate/traitement médicamenteux , Animaux , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/pharmacologie , Benzopyranes/pharmacocinétique , Benzopyranes/pharmacologie , Lignée cellulaire tumorale , Phosphatidylinositol 3-kinase de classe Ia/métabolisme , Chiens , Délétion de gène , Humains , Mâle , Souris nude , Simulation de docking moléculaire , Morpholinos/composition chimique , Morpholinos/pharmacocinétique , Morpholinos/pharmacologie , Morpholinos/usage thérapeutique , Prostate/effets des médicaments et des substances chimiques , Prostate/métabolisme , Tumeurs de la prostate/génétique , Tumeurs de la prostate/métabolisme , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutiqueRÉSUMÉ
We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kß/δ inhibitor: PI3Kß cell IC50 0.012 µM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047 µM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.
Sujet(s)
Antienzymes/composition chimique , Antienzymes/pharmacologie , Isoenzymes/antagonistes et inhibiteurs , Morpholinos/composition chimique , Morpholinos/pharmacologie , Phosphohydrolase PTEN/génétique , Inhibiteurs des phosphoinositide-3 kinases , Animaux , Lignée cellulaire tumorale , Humains , Souris , PhosphorylationRÉSUMÉ
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Sujet(s)
Récepteur alpha des oestrogènes/métabolisme , Ombelliférones/composition chimique , Ombelliférones/pharmacologie , Administration par voie orale , Animaux , Lignée cellulaire tumorale , Coumarines/composition chimique , Coumarines/pharmacocinétique , Coumarines/pharmacologie , Régulation négative/effets des médicaments et des substances chimiques , Récepteur alpha des oestrogènes/analyse , Humains , Simulation de docking moléculaire , Rats , Ombelliférones/pharmacocinétiqueRÉSUMÉ
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kß activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kß/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
Sujet(s)
Dérivés de l'aniline/synthèse chimique , 4H-1-Benzopyran-4-ones/synthèse chimique , Tumeurs expérimentales/traitement médicamenteux , Phosphohydrolase PTEN/déficit , Inhibiteurs des phosphoinositide-3 kinases , Dérivés de l'aniline/pharmacologie , Animaux , 4H-1-Benzopyran-4-ones/pharmacologie , Chiens , Découverte de médicament , Humains , Mâle , Souris , Tumeurs expérimentales/composition chimique , Relation structure-activitéRÉSUMÉ
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Sujet(s)
Amides/pharmacologie , Benzothiazoles/pharmacologie , Douleur/traitement médicamenteux , Canaux cationiques TRPV/antagonistes et inhibiteurs , Amides/administration et posologie , Amides/composition chimique , Animaux , Benzothiazoles/administration et posologie , Benzothiazoles/composition chimique , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Humains , Inflammation/traitement médicamenteux , Structure moléculaire , Rats , Protéines recombinantes/antagonistes et inhibiteurs , Solubilité , Relation structure-activitéRÉSUMÉ
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.