title: Physicochemical and biopharmaceutical characterization of endo-2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one (CR3124) a novel potent 5-HT3 receptor antagonist.
abstract: The physicochemical and biopharmaceutical properties, such as pK(a), crystal habit, water solubility, logD, molecular structure and dynamics, and membrane permeability of CR3124 (endo-2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one, a novel potent 5-HT(3) receptor antagonist) have been studied in order to obtain preformulation information. The study showed that CR3124 is a very rigid molecule in which conformational freedom due to the presence of a rotatable bond is restricted by the interaction between an activated hydrogen and the amide oxygen and the conformation of the tropane piperidine ring is regulated by the environment in such a manner as to optimize the intermolecular interactions with the solvent. This chameleon behavior appears to be capable of explaining the biopharmaceutical properties showed by CR3124, such as low wettability, relatively good solubility, and very high membrane permeability.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Valter
authors.initials: V
authors.lastname: Travagli
authors.forename: Iacopo
authors.initials: I
authors.lastname: Zanardi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Donati
authors.forename: Marianna
authors.initials: M
authors.lastname: Aggravi
authors.forename: Mario
authors.initials: M
authors.lastname: Casolaro
authors.forename: Massimo
authors.initials: M
authors.lastname: Fresta
authors.forename: Eugenio
authors.initials: E
authors.lastname: Paccagnini
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D007408:Intestinal Absorption; D054833:Isoindoles; D008968:Molecular Conformation; D010539:Permeability; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: C517559:CR3124; D007211:Indoles; D054833:Isoindoles; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D014867:Water; D020003:1-Octanol