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.
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.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
Travagli
Valter
V
Zanardi
Iacopo
I
Anzini
Maurizio
M
Giorgi
Gianluca
G
Donati
Alessandro
A
Aggravi
Marianna
M
Casolaro
Mario
M
Fresta
Massimo
M
Paccagnini
Eugenio
E
Makovec
Francesco
F
Vomero
Salvatore
S
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
C517559:CR3124; D007211:Indoles; D054833:Isoindoles; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D014867:Water; D020003:1-Octanol