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Comparison of pre‐clinical pharmacokinetic (PK) and pharmacodynamic (PD) relationships of cannabinoid CB1 receptor antagonists in a drug development program for weight loss (WL) management
Author(s) -
Scott Dennis O,
Hadcock John R,
Black Shawn C
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.711.11
Subject(s) - rimonabant , pharmacology , cannabinoid receptor , cannabinoid , pharmacokinetics , antagonist , antagonism , pharmacodynamics , receptor , chemistry , drug , receptor antagonist , medicine , endocrinology
Background: Establishing PK/PD relationships is critical for drug development. The PK/PD relationship for a CB 1 receptor antagonist program for WL was assessed. Methods: An analysis of PK and PD of in‐house CB 1 antagonists and SR141716 in rats was performed. Results: Receptor occupancy, total plasma and brain concentration, and efficacy (% reduction in food intake [FI] in 2 models of feeding behavior and energy expenditure measured by changes in oxygen consumption [VO 2 ]) were determined in rats. There was a common concentration‐effect relationship across compounds for unbound brain, but not plasma concentrations (Fig 1), that was maintained across efficacy models. Predicted human unbound efficacious plasma concentrations are presented in Table 1. Conclusions: These studies demonstrate that the novel and highly selective CB 1 receptor antagonists CP‐945,598, CE‐178,253, and PF‐431,499 will increase our understanding of the role of CB 1 receptor antagonism in metabolic disease.