Author: Sarkar, Debalina ; King, Aileen J F ; Gilon, Patrick ; Delishaj, Blerinda ; Dereli, Ayse S ; Patterson, Michael ; Bolton, Olivia ; Despontin, Chloe ; Hewawasam, Nirun ; Reeves, Sue ; Hauge-Evans, Astrid C ; Almutairi, Maha

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst−/− mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

01 Mar 2016·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

Q4 · MEDICINE

Article

Author: Zhou, Yun-Ping ; Samuel, Koppara ; Morissette, Pierre ; Shah, Shrenik K ; Chicchi, Gary G ; Hagmann, William K ; Liu, Jian ; Wu, Margaret ; He, Shuwen ; Feng, Zhe ; Nelson, Donald ; Jian, Tianying ; Kerr, Janet ; Fernandez, Guillermo ; Guo, Liangqin ; Zhang, Bei B ; Howard, Andrew D ; Li, Cai ; Ye, Zhixiong ; Nargund, Ravi P ; Trujillo, Maria E ; Fitzgerald, Patrick ; Sherer, Edward ; Trusca, Dorina ; Mitelman, Stan ; Dobbelaar, Peter H ; Bunting, Patricia ; Pasternak, Alexander ; Du, Wu ; Reibarkh, Mikhail ; Truong, Quang ; Hong, Qingmei ; Eiermann, George J ; Tsao, Kwei-Lan ; Reddy, Vijay B ; Qi, Hongbo ; Shao, Qing ; Lin, Melissa ; Volksdorf, Sylvia ; Dellureficio, James D ; Tong, Sharon X ; Bakshi, Raman K

MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

01 Sep 2015·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Q4 · MEDICINE

Article

Author: Trusca, Dorina ; Wu, Zhicai ; Tuang, Quang ; Hong, Qingmei ; He, Shuwen ; Zhou, Yun-Ping ; Guo, Liangqing ; Hagmann, William K ; Yu, Yang ; Howard, Andrew D ; Yang, David X ; Lai, Zhong ; Li, Derun ; Ball, Richard ; Sherer, Edward C ; Tsao, Kwei-Lan ; Nargund, Ravi P ; Chicchi, Gary G

We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Discovery	United States	Merck & Co., Inc.	-

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