Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics.
A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome profiling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl)ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies.
Tao
Zhi-Fu
ZF
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Zhi-Fu.Tao@abbott.com
Chen
Zehan
Z
Bui
Mai-Ha
MH
Kovar
Peter
P
Johnson
Eric
E
Bouska
Jennifer
J
Zhang
Haiying
H
Rosenberg
Saul
S
Sowin
Thomas
T
Lin
Nan-Horng
NH
D000818:Animals; D002384:Catalysis; D000071877:Checkpoint Kinase 1; D006367:HeLa Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011494:Protein Kinases / Q000493:pharmacokinetics / Q000502:physiology; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology
D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse