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Investigation of Cardiovascular Effects of Tetrahydro-?-carboline sstr3 antagonists.


ABSTRACT: Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

SUBMITTER: He S 

PROVIDER: S-EPMC4094257 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists.

He Shuwen S   Lai Zhong Z   Ye Zhixiong Z   Dobbelaar Peter H PH   Shah Shrenik K SK   Truong Quang Q   Du Wu W   Guo Liangqin L   Liu Jian J   Jian Tianying T   Qi Hongbo H   Bakshi Raman K RK   Hong Qingmei Q   Dellureficio James J   Reibarkh Mikhail M   Samuel Koppara K   Reddy Vijay B VB   Mitelman Stan S   Tong Sharon X SX   Chicchi Gary G GG   Tsao Kwei-Lan KL   Trusca Dorina D   Wu Margaret M   Shao Qing Q   Trujillo Maria E ME   Fernandez Guillermo G   Nelson Donald D   Bunting Patricia P   Kerr Janet J   Fitzgerald Patrick P   Morissette Pierre P   Volksdorf Sylvia S   Eiermann George J GJ   Li Cai C   Zhang Bei B   Howard Andrew D AD   Zhou Yun-Ping YP   Nargund Ravi P RP   Hagmann William K WK  

ACS medicinal chemistry letters 20140421 7


Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG c  ...[more]

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