Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors
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- 作者：Philipp Holzer ; Keiichi Masuya ; Pascal Furet ; Joerg Kallen ; Therese Valat-Stachyra ; St茅phane Ferretti ; Joerg Berghausen ; Mich猫le Bouisset-Leonard ; Nicole Buschmann ; Carole Pissot-Soldermann ; Caroline Rynn ; Stephan Ruetz ; Stefan Stutz ; Patrick Ch猫ne ; S茅bastien Jeay ; Francois Gessier
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 27, 2015
- 年：2015
- 卷：58
- 期：16
- 页码：6348-6358
- 全文大小：556K
- ISSN：1520-4804
文摘
As a result of our efforts to discover novel p53:MDM2 protein鈥損rotein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.