Inhibitors of epidermal growth factor receptor tyrosine kinase: optimisation of potency and in vivo pharmacokinetics.
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.
Ballard
Peter
P
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Bradbury
Robert H
RH
Harris
Craig S
CS
Hennequin
Laurent F A
LF
Hickinson
Mark
M
Kettle
Jason G
JG
Kendrew
Jane
J
Klinowska
Teresa
T
Ogilvie
Donald J
DJ
Pearson
Stuart E
SE
Williams
Emma J
EJ
Wilson
Ingrid
I
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry; D000077156:Gefitinib; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013844:Thiazoles; D005461:Fluorine; C027348:2-anilino-5-thiazolinone; D066246:ErbB Receptors; D000077156:Gefitinib