Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists.

Abstract

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...

Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs

“…However, the fact that 2 laboratories molecule. It is interesting to note that the research reported by Stoit et al 13 included in vivo administration of the 3 carbon-bridged compound by intraperitoneal (ip) and oral (po) routes, and the authors reported that no activity was detected, which would be more consistent with a compound that had decreased affi nity as compared with SR141716A. However, it is not clear in their report what measures of pharmacological activity were measured, and as the authors pointed out, the bioavailability of the compounds could be quite different.…”

“…It would be interesting to examine additional analogs, such as the one proposed in Figure 6 , to better approximate the structure of SR141716A. The Stoit, 13 Mussinu, 11 and Murineddu 14 , 15 research groups used carbon bridges to reduce the conformational mobility of t 4 ( Figure 7 , Table 1 ). Initially, Stoit et al 13 reported the 3 carbon-bridged compound and found that it had lower affi nity for the CB1R than SR141716A.…”

“…The Stoit, 13 Mussinu, 11 and Murineddu 14 , 15 research groups used carbon bridges to reduce the conformational mobility of t 4 ( Figure 7 , Table 1 ). Initially, Stoit et al 13 reported the 3 carbon-bridged compound and found that it had lower affi nity for the CB1R than SR141716A. However, Pinna and colleagues 11 , 13 , 14 varied the bridge length from 1 carbon to 3 carbons and reported that the 3 carbon bridged compound, NESS-0327, had fentomolar (fM) affi nity as compared with the nanomolar (nM) affi nity of SR141716A.…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…[105][106][107] Worth mentioning are 105 (OL-1302) with a pentyl chain at the phenyl ring, 108 107 (AM251) obtained by replacing the 5-phenyl chloro substituent by iodine which is used as a reference compound in cannabinoid studies, 109 and 108 (SR147778) which reduced food intake in rats. 110 Besides, different groups have reported conformationally restricted analogs of Rimonabant such as 106, 111 110 with nanomolar affinity for the hCB1 receptor, 112 referred also as NESS0327 in another publication 113 and 111. 31 A patent has been filed for the 5-aryloxypyrazole 109, a CB1 antagonist.…”

Synthesis and reactions of 3-hydrazino-2,3,4,7,8,9-hexahydro-1H-benzo[6',7']cyclohepta[1',2':4,5]pyrido[2,3-d]pyrimidin-1-one

“…They display a wide spectrum of biological activities such as cytotoxic, anticancer agents, [1][2][3][4] as high CB 1 receptors, 5 and have very potent antagonistic activity. 5 Substituted hydrazones are known as one of the most important classes of organic compounds, having analgesic, anticancer, antitumor, anti-inflammatory, antibacterial, and antifungal activities. [6][7][8][9][10][11] In addition, many of the poly-heterocyclic ring systems have several biological activities.…”