Journal Article
Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)
Scott, WJ; Hentemann, MF; Rowley, RB; Bull, CO; Jenkins, S; Bullion, AM; Johnson, J; Redman, A; Robbins, AH; Esler, W; Fracasso, RP; Garrison, T; Hamilton, M; Michels, M; Wood, JE; Wilkie, DP; Xiao, H; Levy, J; Stasik, E; Liu, N; Schaefer, M; Brands, M; Lefranc, J
ChemMedChem
ISSN: 1860-7179
EISSN: 1860-7187
John Wiley and Sons Ltd
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structureâactivity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
copanlisib; lipid kinases; phosphoinositide 3-kinase; PI3K inhibitors; X-ray crystallography; 2 amino 4 (benzyloxy) 3 methoxybenzonitrile; 3 (benzyloxy) 6 (4,5 dihydro 1h imidazol 2 yl) 2 methoxyaniline; 4 (3 chloropropyl)morpholine; 4 (benzyloxy) 3 methoxy 2 nitrobenzaldehyde; 4 (benzyloxy) 3 methoxy 2 nitrobenzonitrile; 4 formyl 2 methoxy 3 nitrophenyl acetate; 4 hydroxy 3 methoxy 2 nitrobenzaldehyde; 8 (benzyloxy) 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 amine; copanlisib; n (7,8 dimethoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl)nicotinamide; n (8 ethoxy 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl)nicotinamide; n (8 hydroxy 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n (8 isobutoxy 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl)nicotinamide; n [7 (allyloxy) 8 [3 (morpholin 4 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 (cyclohexylmethoxy) 8 [3 (morpholin 4 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 hydroxy 8 [3 (morpholin 4 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 isobutoxy 8 [3 (morpholin 4 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 methoxy 8 [2 (morpholin 4 yl)ethoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 methoxy 8 [3 (morpholin 4 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 methoxy 8 [3 (piperidin 1 yl)propoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [7 methoxy 8 [4 (morpholin 4 yl)butoxy] 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [8 (3 aminopropoxy) 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide hydrotrifluoroacetate; n [8 (4 chlorobutoxy) 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [8 (benzyloxy) 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [8 [3 (dimethylamino)propoxy] 7 methoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; n [8 [3 (morpholin 4 yl)propoxy] 7 propoxy 2,3 dihydroimidazo[1,2 c]quinazolin 5 yl]nicotinamide; phosphatidylinositol 3 kinase inhibitor; quinazoline derivative; tert butyl [3 [[7 methoxy 5 [(pyridin 3 ylcarbonyl)amino] 2,3 dihydroimidazo[1,2 c]quinazolin 8 yl]oxy]propyl]carbamate; unclassified drug; unindexed drug; A549 cell line; alkylation; animal cell; antiproliferative activity; Article; breast cancer cell line; drug accumulation; drug identification; drug structure; drug synthesis; enzyme phosphorylation; female; high throughput screening; hydrogen bond; IC50; in vitro study; male; nonhuman; priority journal; rat; structure activity relation