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

Q3 · MEDICINE

Article

Author: Jianmei Pang ; Katie Raustad ; Xiao-Ming Guan ; Ping Liu ; Marc L. Reitman ; Viktor Hornak ; Sheng-Ping Wang ; Theresa M. Kelly ; Alison M. Strack ; Randy Miller ; Yan Guo ; Kathy Lyons ; Yanqing Kan ; Marc Chioda ; Christopher J. Welch ; Ying-Duo Gao ; Jian G. Ning ; Linda Chang ; Judith N. Gorski ; Oksana Palyha ; Jasminka Dragovic ; Donald J. Marsh ; Wes A. Schafer ; Linus S. Lin ; Thomas J. Lanza ; Ravi P. Nargund ; Xiaoyi Gong ; Harry R. Chobanian ; Joseph M. Metzger

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(1) 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.

08 Mar 2012·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

Q3 · MEDICINE

Article

Author: Lin, Linus S. ; Pang, Jianmei ; Dragovic, Jasminka ; Reitman, Marc L. ; Raustad, Kate ; Lanza, Thomas J. ; Strack, Alison M. ; Chioda, Marc ; Chang, Linda ; Guo, Yan ; Metzger, Joseph M. ; Liu, Ping ; Palyha, Oksana ; Lyons, Kathy ; Kelly, Theresa M. ; Nargund, Ravi P. ; Marsh, Donald J. ; Miller, Randy ; Kan, Yanqing ; Wang, Sheng-Ping ; Gorski, Judith N. ; Chobanian, Harry R. ; Guan, Xiao-Ming ; Madeira, Maria

Extensive structure-activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution.

01 Aug 2010·IDrugs : the investigational drugs journal

32nd National Medicinal Chemistry Symposium--medicinal chemistry developments for cancer, and cardiovascular, metabolic and psychiatric disorders.

Author: Gater, Deborah

The 32nd National Medicinal Chemistry Symposium, held in Minneapolis, MN, USA, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on Hsp90 inhibitors and Hsp70 inducers, such as KU-32 and KU-174 (University of Kansas); natural products in drug design, such as minnelide (University of Minnesota) and tylocrebrine; novel compounds from Merck for metabolic and cardiovascular diseases, such as MK-7725, a series of DDP4 inhibitors and KV1.5 ion channel antagonists; and the discovery of the VEGFR2 kinase inhibitor AMG-429 (Amgen Inc).

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	United States	Merck & Co., Inc.	-

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