Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

McBride, Christopher¹  Cheruvallath, Zacharia¹  Komandla, Mallareddy¹  Tang, Mingnam¹  Farrell, Pamela²  Lawson, J. David³  Vanderpool, Darin²  Wu, Yiqin²  Dougan, Douglas R.⁴  Plonowski, Artur²  Holub, Corine²  Larson, Chris² 

[1] Takeda Calif, Med Chem, San Diego, CA USA

[2] Takeda Calif, Biol Sci, San Diego, CA USA

[3] Takeda Calif, Computat Sci, San Diego, CA USA

[4] Takeda Calif, Struct Biol, San Diego, CA USA

关键词: Methionine aminopeptidase-2;    MetAP2;    Metalloprotease;    Fragment-based drug discovery;    FBDD;    Structure-based drug design;    SBDD;    Pyrazolo[4,3-b]indoles;   

DOI  :  10.1016/j.bmcl.2016.04.072

来源: Elsevier

【 摘 要 】

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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