New bicyclic cannabinoid receptor-1 (CB1-R) antagonists

Carpino, Philip A.; Griffith, David A.; Sakya, Subas M.; Dow, Robert L.; Black, Shawn C.; Hadcock, John R.; Iredale, Philip A.; Scott, Dennis O.; Fichtner, Michael; Rose, Colin R.; Day, Robert; DiBrino, Joseph; Butler, Mary; DeBartolo, Demetria B.; Dutcher, Darrin; Gautreau, Denise; Lizano, Jeff S.; O’Connor, Rebecca E.; Sands, Michelle; Kelly-Sullivan, Dawn; Ward, Karen

doi:10.1016/j.bmcl.2005.10.019

Cited by 43 publications

(21 citation statements)

References 9 publications

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“…Acute overnight fast-induced refeeding food intake studies were conducted in male Sprague-Dawley rats as described previously (Carpino et al, 2006). Indirect calorimetry studies in male Sprague-Dawley rats, using an Oxymax indirect calorimeter (Columbus Instruments, Columbus, OH), were conducted as described previously (Harwood et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys

Wagner

Zhang²,

Kavanagh³

et al. 2010

J Pharmacol Exp Ther

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Cannabinoid-1 (CB 1 ) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB 1 receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB 1 -selective antagonist 1-azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n ϭ 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4 -8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pairfed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB 1 receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake.

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Section: Methodsmentioning

confidence: 99%

A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys

Wagner

Zhang²,

Kavanagh³

et al. 2010

J Pharmacol Exp Ther

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“…Analogs of rimonabant that constrain the 3-carboxamide or hydrazide moiety by its incorporation into pyrazole-pyrimidin-7-one (D3a), pyrazole-pyridazin-7-one (D3b), pyrazolo-pyridin-7-one (D3c), or purine-6-one (D3d) ring systems were synthesized and evaluated by Pfizer scientists [Carpino et al, 2006]. Binding affinity in HEK hCB1 transfected cells was high (0.3-38 nM) in spite of the non-alignment of the carboxamide's O, N, and N-substituent when the pyrazole and phenyl rings aligned.…”

Section: Conformationally Constrained Analogsmentioning

confidence: 99%

Recent CB1 cannabinoid receptor antagonists and inverse agonists

Seltzman

2009

Drug Development Research

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Antagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006-2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/ arrange the appended binding/activity elements. A structure-activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one-to-one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70 : 601-615, 2009.

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“…Additional conformational constraint and structural modifi cations of this region were recently reported. 7 Of interest, these molecules constrained the carboxyamide oxygen atom in the s-cis position and still retained reasonable affi nities. The most analogous molecule to SR141716A, compound 2b ( Figure 4 ), which has only hydrogen bond accepting capability, exhibited surprisingly high affi nities despite the poor overlap of the piperidinyl groups in the low-energy conformer of SR141716.…”

Section: E666mentioning

confidence: 99%

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

Thomas

Zhang

Brackeen

et al. 2006

AAPS J

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Interest in cannabinoid pharmacology increased dramatically upon the identifi cation of the fi rst cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the fi rst potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated effi cacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate. At this time, medicinal chemistry approaches including combinatorial chemistry, conformational constraint, and scaffold hopping are continuing to generate a large number of cannabinoid antagonists. These molecules provide an opportunity to gain insight into the 3-dimensional structure-activity relationships that appear crucial for CB1R-ligand interaction. In particular, studies in which conformational constraints have been imposed on the various pyrazole ring substituents of SR141716A provide a direct opportunity to characterize changes in conformation/ conformational freedom within a single class of compounds. While relatively few conformationally constrained molecules have been synthesized to date, the structureactivity information is often more readily interpreted than in studies where entire substituents are replaced. Thus, it is the focus of this mini-review to examine the structural properties of SR141716A, and to use conformationally constrained molecules to illustrate the importance of conformation and conformational freedom to CB1R affi nity, selectivity, and effi cacy.

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New bicyclic cannabinoid receptor-1 (CB1-R) antagonists

Cited by 43 publications

References 9 publications

A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys

A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys

Recent CB1 cannabinoid receptor antagonists and inverse agonists

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

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