title: Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) 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.
authors.affiliation: Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com
authors.forename: Jos H M
authors.initials: JH
authors.lastname: Lange
authors.forename: Hein K A C
authors.initials: HK
authors.lastname: Coolen
authors.forename: Herman H
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Jessica A R
authors.initials: JA
authors.lastname: Dijksman
authors.forename: Arnoud H J
authors.initials: AH
authors.lastname: Herremans
authors.forename: Eric
authors.initials: E
authors.lastname: Ronken
authors.forename: Hiskias G
authors.initials: HG
authors.lastname: Keizer
authors.forename: Koos
authors.initials: K
authors.lastname: Tipker
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.forename: Willem
authors.initials: W
authors.lastname: Veerman
authors.forename: Henri C
authors.initials: HC
authors.lastname: Wals
authors.forename: Bob
authors.initials: B
authors.lastname: Stork
authors.forename: Peter C
authors.initials: PC
authors.lastname: Verveer
authors.forename: Arnold P
authors.initials: AP
authors.lastname: den Hartog
authors.forename: Natasja M J
authors.initials: NM
authors.lastname: de Jong
authors.forename: Tiny J P
authors.initials: TJ
authors.lastname: Adolfs
authors.forename: Jan
authors.initials: J
authors.lastname: Hoogendoorn
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C482795:3-(4-chlorophenyl)-N-methyl-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; D016718:Arachidonic Acid