Synthesis, Biological Properties, and Molecular Modeling Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selective CB₁ Cannabinoid Receptor Antagonists

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.

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

“…Rimonabant successful development encouraged searching for selective CB1 receptor ligands as new chemical entities with similar or better pharmacological and safety profiles as compared to rimonabant [16,56,57,[66][67][68][69]. Biosiosteric replacements and substituent modifications of the rimonabant pyrazole pharmacophore as well as de novo and highthroughout screening approaches have indeed generated many novel CB1 receptor ligands acting as neutral antagonists or inverse agonists.…”

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…In addition to rimonabant, several other CB1-receptor antagonists have been synthesized, and many are under development, but at present little is known about them. 44 …”

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

“…There is an overwhelming evidence indicating that various heterocyclic cores attached to a diaryl system possess diverse pharmacological activities viz., COX II inhibition [4], allosteric modulation of GABA A receptor [5] and estrogen receptor [6], adenosine receptor antagonism [7], selective p38a inhibition [8], cannabinoid receptor antagonism [9], antimitotic activity [10] (combretastatin analogs), antiplatelet activity [11] and anti-HIV-1 activity [12] (TMC-125).…”