Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Abstract

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

• Authors: Xiaozhang Zheng, Kenneth W Bair, Paul Bauer, Timm Baumeister, Krista K Bowman, Alexandre J Buckmelter, Maureen Caligiuri, Karl H Clodfelter, Yezhen Feng, Bingsong Han, Yen-Ching Ho, Nikolai Kley, Hong Li, Xiaorong Liang, Bianca M Liederer, Jian Lin, Justin Ly, Thomas O'Brien, Jason Oeh, Angela Oh, Dominic J Reynolds, Deepak Sampath, Geeta Sharma, Nicholas Skelton, Chase C Smith, Jarrod Tremayne, Leslie Wang, Weiru Wang, Zhongguo Wang, Hongxing Wu, Jiansheng Wu, Yang Xiao, Guangxing Yang, Po-wai Yuen, Mark Zak, Peter S Dragovich
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 20 Pg. 5488-97 (Oct 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 24021463 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Carboxylic Acids
• Cytokines
• Enzyme Inhibitors
• Pyrazoles
• Pyridines
• Sulfones
• pyrazolo(3,4-b)pyridine
• NAD
• Niacinamide
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, human

Topics

• Amides (chemical synthesis, chemistry, pharmacokinetics)
• Animals
• Binding Sites
• Carboxylic Acids (chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Cytokines (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacokinetics)
• Female
• Half-Life
• Haplorhini
• Humans
• Mice
• Mice, Nude
• NAD (metabolism)
• Niacinamide (analogs & derivatives, blood, chemistry, pharmacokinetics)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, metabolism)
• Protein Structure, Tertiary
• Pyrazoles (blood, chemistry, pharmacokinetics)
• Pyridines (chemistry)
• Rats
• Retina (drug effects, metabolism)
• Structure-Activity Relationship
• Sulfones (blood, chemistry, pharmacokinetics)
• Transplantation, Heterologous