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.

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.

Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries.1,2) However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on CB receptors and their (endogenous) agonists. The discovery and the subsequent cloning 3,4) of two subtypes of cannabinoid receptor (CB 1 and CB 2 ) stimulated the search for novel cannabinoid antagonists and triggered the development of cannabinoid drugs for the treatment of diseases. 5,6) Several types of CB 1 receptor antagonists are known (Fig. 1). Sanofi disclosed 7-9) their selective CB 1 receptor antagonist SR141716A (rimonabant) which is currently undergoing clinical development for psychotic disorders and obesity treatment. Iodopravadoline AM-630 was introduced in 1995. AM-630 is a moderately active CB 1 receptor antagonist, but sometimes behaves as a weak partial agonist. 10) Researchers from Eli Lilly described 11) the selective CB 1 receptor antagonist LY-320135. 3-Alkyl-5,5Ј-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated 12) to be cannabinoid antagonists. CP-272871 is a pyrazole derivative, like SR141716A, but less potent and less CB 1 receptor subtype-selective 13) than SR141716A. Recently, Aventis Pharma claimed 14) diarylmethyleneazetidine analogs (1) as CB 1 receptor antagonists. Interestingly, many CB 1 receptor antagonists have been reported 15) to behave as inverse agonists in vitro. Several reviews describe the current status in the cannabinoid research area. [16][17][18][19] In this paper our approach to tricyclic selective CB 1 receptor antagonists of general formula (2) is described. 20) We envisioned that an additional ring constraint from the 4-methyl position in SR141716A to the ortho-position of its 5-aryl substituent would provide a novel class of considerably more rigid benzocycloheptapyrazoles (2), thereby having good prospects as potent CB 1 antagonists. Moreover, threedimensional comparison of SR141716A with the more rigid counterpart (2) and analysis of their pharmacological results is expected to provide a more detailed insight in the required bioactive conformation of such CB 1 receptor antagonists, which is expected to facilitate their rational structure optimisation. ChemistryThe four step synthesis route to the CB 1 antagonists (2) is exemplified by the preparation of 8 (Chart 1). Commercially available 1-benzosuberone (3) was deprotonated with lithium bis(trimethylsilyl)amide and subsequently reacted with diethyl oxalate to afford the lithiated keto ester adduct (4) as a solid in 99% yield. Subsequent reaction with the arylhydrazine (5) in acetic acid gave the benzocycloheptapyrazole ester (6) in 51% yield. Mild basic hydrolysis of the carboethoxy group in 6 to the corresponding carboxylic acid proceeded quantitatively. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC)-activated coupling to Naminoperhydroazepine (7) in dichloromethane furnished 8 in 68% yield.In this specific cas...

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.

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