7062-49-9Relevant articles and documents
Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis
Iyer, Malliga R.,Cinar, Resat,Katz, Alexis,Gao, Michael,Erdelyi, Katalin,Jourdan, Tony,Coffey, Nathan J.,Pacher, Pal,Kunos, George
, p. 1126 - 1141 (2017/02/19)
We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB1Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism.
Synthesis, Biological Properties, and Molecular Modeling Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selective CB1 Cannabinoid Receptor Antagonists
Lange, Jos H. M.,Coolen, Hein K. A. C.,Van Stuivenberg, Herman H.,Dijksman, Jessica A. R.,Herremans, Arnoud H. J.,Ronken, Eric,Keizer, Hiskias G.,Tipker, Koos,McCreary, Andrew C.,Veerman, Willem,Wals, Henri C.,Stork, Bob,Verveer, Peter C.,Den Hartog, Arnold P.,De Jong, Natasja M. J.,Adolfs, Tiny J. P.,Hoogendoorn, Jan,Kruse, Chris G.
, p. 627 - 643 (2007/10/03)
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB1 antagonistic activities and in general exhibited high CB1 vs CB2 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 C4 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 CB1 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 -NH2 moiety with a -NHCH3 group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
