Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors.
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48106-1047, USA.
Sylvester R
SR
Klutchko
Hairong
H
Zhou
R Thomas
RT
Winters
Tuan P
TP
Tran
Alexander J
AJ
Bridges
Irene W
IW
Althaus
Danielle M
DM
Amato
William L
WL
Elliott
Paul A
PA
Ellis
Mary Ann
MA
Meade
Billy J
BJ
Roberts
David W
DW
Fry
Andrea J
AJ
Gonzales
Patricia J
PJ
Harvey
James M
JM
Nelson
Veronica
V
Sherwood
Hyo-Kyung
HK
Han
Gerry
G
Pace
Jeff B
JB
Smaill
William A
WA
Denny
H D Hollis
HD
Showalter
D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010766:Phosphorylation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D066247:Receptor, ErbB-4; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000480:Alkynes; D000577:Amides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011743:Pyrimidines; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat