Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 16; pp. 4511 - 4516
• Main Authors: Hornberger, Keith R., Chen, Xin, Crew, Andrew P., Kleinberg, Andrew, Ma, Lifu, Mulvihill, Mark J., Wang, Jing, Wilde, Victoria L., Albertella, Mark, Bittner, Mark, Cooke, Andrew, Kadhim, Salam, Kahler, Jennifer, Maresca, Paul, May, Earl, Meyn, Peter, Romashko, Darlene, Tokar, Brianna, Turton, Roy
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2013; Elsevier
• Subjects: 7-Amino-furo[2,3-c]pyridine; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animal models; Animals; Cancer; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Humans; Inflammation; Inhibitors; Inhibitory Concentration 50; Life Sciences & Biomedicine; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Molecular Structure; Neoplasms - drug therapy; Pharmacology & Pharmacy; Phosphotransferases - chemistry; Phosphotransferases - metabolism; Physical Sciences; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; TAK1; Xenograft Model Antitumor Assays; 7-Amino-furo[2,3-c]pyridine; Inflammation; Inhibitors; TAK1; Cancer; VEGF
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.054

The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.