The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization

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• 作者：Harry R. Chobanian^a ; ^{harry_chobanian@merck.com} ; Yan Guo^a ; Ping Liu^a ; Thomas J. Lanza Jr.^a ; Marc Chioda^a ; Linda Chang^a ; Theresa M. Kelly^b ; Yanqing Kan^b ; Oksana Palyha^b ; Xiao-Ming Guan^b ; Donald J. Marsh^b ; Joseph M. Metzger^c ; Katie Raustad^c ; Sheng-Ping Wang^c ; Alison M. Strack^c ; Judith N. Gorski^c ; Randy Miller^d ; Jianmei Pang^d ; Kathy Lyons^d ; Jasminka Dragovic^d ; Jian G. Ning^e ; Wes A. Schafer^e ; Christopher J. Welch^e ; Xiaoyi Gong^e ; Ying-Duo Gao^f ; Viktor Hornak^f ; Marc L. Reitman^b ; Ravi P. Nargund^a ; Linus S. Lin^a
• 关键词：Bombesin receptor subtype-3 (BRS-3) ; Agonist ; Obesity ; Atropisomerism ; Benzodiazepine sulfonamide
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 May, 2012
• 年：2012
• 卷：20
• 期：9
• 页码：2845-2849
• 全文大小：342 K

文摘

Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725 Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.