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Bioorg Med Chem Lett. 2016 Jun 15;26(12):2779-2783. doi: 10.1016/j.bmcl.2016.04.072. Epub 2016 Apr 25.

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

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Medicinal Chemistry, Takeda California, United States.
Biological Sciences, Takeda California, United States.
Computational Sciences, Takeda California, United States.
Structural Biology, Takeda California, United States.


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.


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


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