Discovery and Pharmacological Evaluation of Growth Hormone Secretagogue Receptor Antagonists

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DH...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (15), p.4459-4469
Main Authors: Xin, Zhili, Serby, Michael D, Zhao, Hongyu, Kosogof, Christi, Szczepankiewicz, Bruce G, Liu, Mei, Hutchins, Charles W, Sarris, Kathy A, Hoff, Ethan D, Falls, H. Douglas, Lin, Chun W, Ogiela, Christopher A, Collins, Christine A, Brune, Michael E, Bush, Eugene N, Droz, Brian A, Fey, Thomas A, Knourek-Segel, Victoria E, Shapiro, Robin, Jacobson, Peer B, Beno, David W. A, Turner, Teresa M, Sham, Hing L, Liu, Gang
Format: Article
Language:English
Subjects:
Administration, Oral
Amides - chemical synthesis
Amides - pharmacology
Aminopyridines - chemical synthesis
Aminopyridines - pharmacology
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - pharmacology
Appetite Depressants - chemical synthesis
Appetite Depressants - pharmacology
Biological and medical sciences
Biological Availability
Body Weight - drug effects
Cell Line
Crystallography, X-Ray
Eating - drug effects
General and cellular metabolism. Vitamins
Hormones. Endocrine system
Humans
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Obese
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, Ghrelin
Structure-Activity Relationship
Urea - analogs & derivatives
Urea - chemical synthesis
Urea - pharmacology
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Summary:The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060461g