ABSTRACT
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
Subject(s)
Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Arachidonic Acid/metabolism , Binding, Competitive , Biological Availability , CHO Cells , Cricetinae , Crystallography, X-Ray , Fever/chemically induced , Fever/physiopathology , Humans , Hypotension/chemically induced , Hypotension/physiopathology , Male , Mice , Models, Molecular , Molecular Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
In this paper, SLV310 is presented as a novel, potential antipsychotic displaying the interesting combination of potent dopamine D(2) receptor antagonism and serotonin reuptake receptor inhibition in one molecule. As such, SLV310 could be useful in treating a broad range of symptoms in schizophrenia. This paper describes the structure-activity relationship in a series of compounds leading to SLV310 (6b, 2-[4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl]-phthalimide) together with pharmacological data showing the unique profile of this compound.
Subject(s)
Antipsychotic Agents/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Phthalimides/chemical synthesis , Phthalimides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , 5-Hydroxytryptophan/pharmacology , Animals , Apomorphine/antagonists & inhibitors , Behavior, Animal/drug effects , CHO Cells , Cricetinae , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Humans , Indicators and Reagents , Mice , Motor Activity/drug effects , Structure-Activity RelationshipABSTRACT
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.2) as well as very potent antagonistic activity (pA2=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.
