The preparation and sar of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56lck and EGF-R tyrosine kinase activity

Myers, Michael R.; Setzer, Natalie N.; Spada, Alfred P.; Zulli, Allison L.; Hsu, Chin-Yi Jenny; Zilberstein, Asher; Johnson, Susan E.; Hook, Linda E.; Jacoski, Mary V.

doi:10.1016/s0960-894x(97)00034-6

Cited by 49 publications

(22 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13] , 6 – 9 [14] , [15] , [16] , 20 – 21 [13] , 25 [13] , 28 [17] and 30 [18] are in agreement with those reported in the literature.…”

Section: Methodssupporting

confidence: 85%

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Newton

Bowler

Burns

et al. 2016

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

show abstract

Section: Methodssupporting

confidence: 85%

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Newton

Bowler

Burns

et al. 2016

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…-7-one(22). To a solution of 20 (206 mg, 0.73 mmol) in 30 mL of CHCl 3 was added 50-60% mchloroperbenzoic acid (600 mg, 1.74-2.09 mmol).…”

mentioning

confidence: 99%

Synthesis and Tyrosine Kinase Inhibitory Activity of a Series of 2-Amino-8H-pyrido[2,3-d]pyrimidines: Identification of Potent, Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitors

Boschelli¹,

Wu²,

Klutchko³

et al. 1998

J. Med. Chem.

View full text Add to dashboard Cite

Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.

show abstract

“…2-Amino-substituted quinazolinones are nanomolar inhibitors of p56 lck and EGF-R tyrosine kinase and thymidylate synthase [34] [35].…”

Section: M Vˆgtle and A L Marzinzikmentioning

confidence: 99%

Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase

Vögtle¹,

Marzinzik²

2004

QSAR Comb. Sci.

View full text Add to dashboard Cite

Full PaperQuinazolines are a pharmacologically very attractive class of compounds and have shown activity in various assays. Several successfully launched drugs are based on this scaffold. As a consequence, a more intensive exploitation in drug discovery by solid-phase syntheses of quinazoline libraries has been initiated. A diverse array of combinatorial quinazoline syntheses have been published and an increasing effort is to be expected in the near future to provide more efficient solid phase approaches towards quinazolines, quinazolinones and quinazolinediones. This review summarizes the literature published until January 2004 describing methods for synthesis and modification of these compounds on solid phase.

show abstract

The preparation and sar of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56lck and EGF-R tyrosine kinase activity

Cited by 49 publications

References 22 publications

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Synthesis and Tyrosine Kinase Inhibitory Activity of a Series of 2-Amino-8H-pyrido[2,3-d]pyrimidines: Identification of Potent, Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitors

Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase

Contact Info

Product

Resources

About