RÉSUMÉ
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Sujet(s)
Régulation négative/effets des médicaments et des substances chimiques , Découverte de médicament , Tumeurs de la prostate/traitement médicamenteux , Pyridazines/pharmacologie , Récepteurs aux androgènes/métabolisme , Bibliothèques de petites molécules/pharmacologie , Animaux , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Mâle , Structure moléculaire , Tumeurs de la prostate/anatomopathologie , Pyridazines/synthèse chimique , Pyridazines/composition chimique , Bibliothèques de petites molécules/synthèse chimique , Bibliothèques de petites molécules/composition chimique , Relation structure-activitéRÉSUMÉ
The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
Sujet(s)
Antinéoplasiques/synthèse chimique , Organophosphates/synthèse chimique , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Pyrazoles/synthèse chimique , Quinazolines/synthèse chimique , Animaux , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/pharmacologie , Aurora kinase A , Aurora kinase B , Aurora kinases , Division cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Inhibiteurs des enzymes du cytochrome P-450 , Tests de criblage d'agents antitumoraux , Canal potassique ERG1 , Canaux potassiques éther-à-go-go/effets des médicaments et des substances chimiques , Femelle , Histone/métabolisme , Humains , Mâle , Souris , Souris nude , Organophosphates/pharmacocinétique , Organophosphates/pharmacologie , Phosphorylation , Promédicaments/synthèse chimique , Promédicaments/pharmacocinétique , Promédicaments/pharmacologie , Liaison aux protéines , Pyrazoles/pharmacocinétique , Pyrazoles/pharmacologie , Quinazolines/pharmacocinétique , Quinazolines/pharmacologie , Rats , Protéines recombinantes/antagonistes et inhibiteurs , Relation structure-activité , Transplantation hétérologueRÉSUMÉ
Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.