Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists

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 representat...

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Veröffentlicht in:Journal of medicinal chemistry 2004-01, Vol.47 (3), p.627
Hauptverfasser: 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
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container_issue 3
container_start_page 627
container_title Journal of medicinal chemistry
container_volume 47
creator 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
description 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.
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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. 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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.</abstract><cop>United States</cop><pmid>14736243</pmid></addata></record>
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subjects 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 - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Radioligand Assay
Rats
Receptor, Cannabinoid, CB1 - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
title Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists
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