title: Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
abstract: Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Jeff B
authors.initials: JB
authors.lastname: Smaill
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Gonzales
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Reed
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Sexton
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Irene W
authors.initials: IW
authors.lastname: Althaus
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Black
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ellis
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fakhoury
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Harvey
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Hook
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Florence O J
authors.initials: FO
authors.lastname: McCarthy
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Freddy
authors.initials: F
authors.lastname: Rivault
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schlosser
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ellis
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Trachet
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Winters
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Haile
authors.initials: H
authors.lastname: Tecle
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories , 2800 Plymouth Road, Ann Arbor, Michigan 48105-1047, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bridges
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D064593:Heterografts; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008819:Mice, Nude; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D052999:Quinazolinones; C525726:dacomitinib; C420268:Canertinib; D066246:ErbB Receptors