RESUMO
The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Fenilalanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Peptídeos/química , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacocinética , Ligação Proteica , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos , Descoberta de Drogas , Amidas/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Células Cultivadas , Ciclização , Humanos , Fígado/metabolismo , Estrutura Molecular , Ligação Proteica/efeitos dos fármacosRESUMO
The asymmetric unit of the anhydrous title compound, 2Na(+)·C(4)H(4)O(6) (2-), contains two sodium cations and one tartrate anion. Each sodium ion is six coordinate, with bonding to six O atoms from both the carboxyl-ate and hydroxyl groups of the anion. A three-dimensional coordination network is formed with sodium ions stacking in layers along the c-axis direction. This network is supported by additional O-Hâ¯O hydrogen bonds.
RESUMO
THE ASYMMETRIC UNIT OF THE TITLE COMPOUND [SYSTEMATIC NAME: (R,R)-2,4-bis-(4-hydroxy-phen-yl)-N,N'-dimethyl-3-oxapentane-1,5-diammonium bis-(hydrogen sulfate)], C(18)H(26)N(2)O(3) (2+)·2HSO(4) (-), contains one half-cation and one hydrogen sulfate anion. The cation has crystallographically imposed twofold symmetry with the rotation axis passing through the central ether O atom. Hydrogen bonds between the hydr-oxy group and amine H atoms of the cation to two hydrogen sulfate anions link the three ions in a ring motif. A three-dimensional network is accomplished by additional O-Hâ¯O hydrogen bonds between the anions and by N-Hâ¯O hydrogen bonds between the cations. Disorder with equally occupied sites affects the H-atom position in the anion.