Identification of piperazine-bisamide GHSR antagonists for the treatment of obesity

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 5, 2010, Pages 1758-1762

  Yu, Ming ^a   Lizarzaburu, Mike ^a   Beckmann, Holger ^a   Connors, Richard ^a   Dai, Kang ^a   Haller, Katrin ^b   Li, Cong ^a   Liang, Lingming ^a   Lindstrom, Michelle ^a   Ma, Ji ^a   Motani, Alykhan ^a   Wanska, Malgorzata ^a   Zhang, Alex ^a   Li, Leping ^c   Medina, Julio C ^a  

^a AMGEN INC   (United States)

^b INNOCOLL GmbH   (Germany)

^c Presidio Pharmaceuticals Inc   (United States)

Author keywords

Agonist; Antagonist; Ghrelin; Growth hormone secretagogue receptor (GHSR); Inositol phosphate (IP) assay; Piperazine bisamide; Pituitary assay

Indexed keywords

ANTIOBESITY AGENT; GHRELIN; GROWTH HORMONE SECRETAGOGUE RECEPTOR; PIPERAZINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; APPETITE; ARTICLE; CHO CELL; DRUG STRUCTURE; FOOD INTAKE; HIGH THROUGHPUT SCREENING; HORMONE BLOOD LEVEL; HUMAN; IN VIVO STUDY; NONHUMAN; OBESITY; RAT; REGULATORY MECHANISM; STRUCTURE ACTIVITY RELATION;

AMIDES; ANIMALS; ANTI-OBESITY AGENTS; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; INDOLES; OBESITY; PIPERAZINES; RATS; RECEPTORS, GHRELIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 76649095334     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.043     Document Type: Article

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37. Compound 1a also behaved as a partial agonist in the IP assay with CHO cells stably expressing rat GHSR. In this assay 1a was evaluated at 10 μM, 1.0 μM, and 0.1 μM and afforded a 14%, 14%, and 24% in IP accumulation relative to ghrelin's maximal response, respectively.
38. 50 > 10 μM).
39. Compound 3h afforded a 33%, 42%, and 41% relative to ghrelin's maximal increase in the IP assay using CHO cells stably expressing rat GHSR at 10 μM, 1.0 μM, and 0.1 μM, respectively.
40. The assay protocol was as the following: pituitary cells freshly collected from 6-8 weeks old male SD rats were plated onto 96-well poly-d-lysine coated plates and incubated at 37 °C for 3 days. The cells were then washed with DMEM assay buffer containing 20 mM Hepes and 0.3% BSA, and incubated at 37 °C for 5 min. For agonist activity experiment, the cells were treated with rat ghrelin or subject compounds for 20 min. For antagonist activity experiment (8b), the cells were pretreated with the subject compounds for 10 min before co-incubation with rat ghrelin and the subject compounds for additional 20 min. The sample was taken for rat growth hormone secretion readout by RIA assay (LINCO Research).
41. +.
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