RÉSUMÉ
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.
Sujet(s)
Conception de médicament , Éthers/pharmacologie , Inhibiteurs de la phosphodiestérase/pharmacologie , Phosphodiesterases/métabolisme , Pyrazines/pharmacologie , Pyridines/pharmacologie , Animaux , Chiens , Relation dose-effet des médicaments , Éthers/administration et posologie , Éthers/composition chimique , Haplorhini , Humains , Mâle , Souris , Structure moléculaire , Inhibiteurs de la phosphodiestérase/administration et posologie , Inhibiteurs de la phosphodiestérase/composition chimique , Pyrazines/administration et posologie , Pyrazines/composition chimique , Pyridines/administration et posologie , Pyridines/composition chimique , Rats , Rat Sprague-Dawley , Relation structure-activitéRÉSUMÉ
Excision of Mullerian structures in children with disorders of sexual differentiation is an operative challenge. We report our experience with laparoscopic excision of Mullerian structures in a neonate with mixed gonadal dysgenesis. The salient features of the procedure were excellent visualisation and ease of dissection.