Discovery of MK-1421, a Potent, Selective Sstr3 Antagonist, As a Development Candidate for Type 2 Diabetes

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2015 May 26

PMID 26005524

Citations 7

Authors

Shrenik K Shah

Shuwen He

Liangqin Guo

Quang Truong

Hongbo Qi

Wu Du

Zhong Lai

Jian Liu

Tianying Jian

Qingmei Hong

Peter Dobbelaar

Zhixiong Ye

Edward Sherer

Zhe Feng

Yang Yu

Frederick Wong

Koppara Samuel

Maria Madiera

Bindhu V Karanam

Vijay B Reddy

Stan Mitelman

Sharon X Tong

Gary G Chicchi

Kwei-Lan Tsao

Dorina Trusca

Yue Feng

Margaret Wu

Qing Shao

Maria E Trujillo

George J Eiermann

Cai Li

Michele Pachanski

Guillermo Fernandez

Donald Nelson

Patricia Bunting

Pierre Morissette

Sylvia Volksdorf

Janet Kerr

Bei B Zhang

Andrew D Howard

Yun-Ping Zhou

Alexander Pasternak

Ravi P Nargund

William K Hagmann

Affiliations

Soon will be listed here.

Abstract

The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).

Citing Articles

Beta cell primary cilia mediate somatostatin responsiveness via SSTR3.

Adamson S, Li Z, Hughes J Islets. 2023; 15(1):2252855.

PMID: 37660302 PMC: 10478741. DOI: 10.1080/19382014.2023.2252855.

Bioinformatics Analysis of Next Generation Sequencing Data Identifies Molecular Biomarkers Associated With Type 2 Diabetes Mellitus.

Alur V, Raju V, Vastrad B, Vastrad C, Kavatagimath S, Kotturshetti S Clin Med Insights Endocrinol Diabetes. 2023; 16:11795514231155635.

PMID: 36844983 PMC: 9944228. DOI: 10.1177/11795514231155635.

HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails.

Barbeito P, Tachibana Y, Martin-Morales R, Moreno P, Mykytyn K, Kobayashi T Life Sci Alliance. 2020; 4(3).

PMID: 33372037 PMC: 7772773. DOI: 10.26508/lsa.202000746.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.

Gunther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp H Pharmacol Rev. 2018; 70(4):763-835.

PMID: 30232095 PMC: 6148080. DOI: 10.1124/pr.117.015388.

Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A-E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium.

Al-Awadhi F, Gao B, Rezaei M, Kwan J, Li C, Ye T J Med Chem. 2018; 61(14):6364-6378.

PMID: 30015488 PMC: 7341966. DOI: 10.1021/acs.jmedchem.8b00885.

References

Jamieson C, Moir E, Rankovic Z, Wishart G . Medicinal chemistry of hERG optimizations: Highlights and hang-ups. J Med Chem. 2006; 49(17):5029-46. DOI: 10.1021/jm060379l. View

He S, Ye Z, Truong Q, Shah S, Du W, Guo L . The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes. ACS Med Chem Lett. 2014; 3(6):484-9. PMC: 4025728. DOI: 10.1021/ml300063m. View

Tashibu H, Miyazaki H, Aoki K, Akie Y, Yamamoto K . QT PRODACT: in vivo QT assay in anesthetized dog for detecting the potential for QT interval prolongation by human pharmaceuticals. J Pharmacol Sci. 2006; 99(5):473-86. DOI: 10.1254/jphs.qt-a3. View

Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Haruna M . QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals. J Pharmacol Sci. 2006; 99(5):459-71. DOI: 10.1254/jphs.qt-a2. View

Cavalli A, Poluzzi E, De Ponti F, Recanatini M . Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002; 45(18):3844-53. DOI: 10.1021/jm0208875. View

He H, Lyons K, Shen X, Yao Z, Bleasby K, Chan G . Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure. Xenobiotica. 2009; 39(9):687-93. DOI: 10.1080/00498250903015402. View

Morissette P, Nishida M, Trepakova E, Imredy J, Lagrutta A, Chaves A . The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model. J Pharmacol Toxicol Methods. 2013; 68(1):137-49. DOI: 10.1016/j.vascn.2013.04.010. View

He S, Lai Z, Ye Z, Dobbelaar P, Shah S, Truong Q . Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists. ACS Med Chem Lett. 2014; 5(7):748-53. PMC: 4094257. DOI: 10.1021/ml500028c. View

Sanguinetti M, Mitcheson J . Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci. 2005; 26(3):119-24. DOI: 10.1016/j.tips.2005.01.003. View

10.

Poitout L, Roubert P, Moinet C, Lannoy J, Pommier J, Plas P . Identification of potent non-peptide somatostatin antagonists with sst(3) selectivity. J Med Chem. 2001; 44(18):2990-3000. DOI: 10.1021/jm0108449. View

11.

Pasternak A, Feng Z, de Jesus R, Ye Z, He S, Dobbelaar P . Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist. ACS Med Chem Lett. 2014; 3(4):289-93. PMC: 4025754. DOI: 10.1021/ml200272z. View

12.

Blum C, Zheng X, De Lombaert S . Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists. J Med Chem. 2004; 47(9):2318-25. DOI: 10.1021/jm030490g. View