Full Download Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,⁷.1⁹,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles. - HJ Breslin Affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, United States. HBreslin60@gmail.com; BM Lane; GR Ott; AK Ghose; TS Angeles; All authors | PDF Online

Document Type: Article All Authors / Contributors: HJ Breslin Affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, United States. HBreslin60@gmail.com; BM Lane; GR Ott; AK Ghose; TS Angeles; MS Albom; M Cheng; W Wan; RC Haltiwanger; KJ Wells-Knecht; BD Dorsey ISSN:0022-2623 Language Note: English Unique Identifier: 776317623 Awards: Abstract: A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted U shaped conformation of the acyclic DAPs is a preferred bioactive conformation.