Development of methyl isoxazoleazepines as inhibitors of BET. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Hewitt, Michael C.; Leblanc, Yves; Gehling, Victor S.; Vaswani, Rishi G.; Côté, Alexandre; Nasveschuk, Christopher G.; Taylor, Alexander M.; Harmange, Jean-Christophe; Audia, James E.; Pardo, Eneida; Cummings, Rich; Joshi, Shivangi; Sandy, Peter; Mertz, Jennifer A.; Sims, Robert J.; Bergeron, Louise; Bryant, Barbara M.; Bellon, Steve; Poy, Florence; Jayaram, Hariharan; Tang, Yong; Albrecht, Brian K.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 9(2015)
• Page Start: 1842
• Page End: 1848
• Publication Date: 2015-05-01
• Subjects: BET inhibitors -- Bromodomains -- Isoxazoles -- MYC -- Unbound clearance; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.045
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified byCPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide23 . The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.