Cis-Amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase

• Published in: Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.897-901
• Main Authors: Staben, Steven T., Blaquiere, Nicole, Tsui, Vickie, Kolesnikov, Aleksandr, Do, Steven, Bradley, Erin K., Dotson, Jenna, Goldsmith, Richard, Heffron, Timothy P., Lesnick, John, Lewis, Cristina, Murray, Jeremy, Nonomiya, Jim, Olivero, Alan G., Pang, Jodie, Rouge, Lionel, Salphati, Laurent, Wei, BinQing, Wiesmann, Christian, Wu, Ping
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; aniline; Benzothiazoles - chemistry; Benzoxepins - chemical synthesis; Benzoxepins - chemistry; Benzoxepins - pharmacology; Binding Sites; bioavailability; Crystallography, X-Ray; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Isostere; Models, Molecular; permeability; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; PI3-kinase; Property-guided design; solubility; Structure-based design; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.121

Substructural class effects surrounding replacement of a ‘cis’N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.