Quinazoline inhibitors

R. W. Ward, J. White, E. W. Moomaw, C. A. Bartlett, and C. A. Morse, Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase, J. Med. Chem. 39 904 (1996). 

Marelius J, GraffnerNordberg M, Hansson T, Hallberg A, Aqvist J. 1998. Computation of affinity and selectivity binding of 2,4-diaminopteridine and 2,4-diamino-quinazoline inhibitors to dihydrofolate reductases. J. Comput.-AidedMolec. Des. 12 119-31... 

The second case used the binding of a series of quinazoline inhibitors to S. faecium dihydrofolate reductase (269). In this case, six site points were used to represent the binding site of the dihydrofolate reductase and the data for 22 inhibitors were correlated. Again the site points and ligand were compared with the only available crystal study at the time, a methotrexate complex of E. coli dihydrofolate reductase, and shown to be consistent. 

An expanded analysis of 68 quinazoline inhibitors of DHFR using this improved technique gave a RMS (root mean square) difference between observed and calculated fits of 1.33 kcal (experimental error about 1 kcal) (271). In addition to this correlation, the possibility of a variable binding mode of some inhibitors was noted and some suggestions were made to modify these quinazolines to make tighter binding ligands. 

Griffin RJ, Srinivasan S, Bowman K et al. Resistance-modifying agents. 5. Synthesis and biolr cal properties of quinazoline inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). J Med Chem 1998 41 5247-5256. 

A series of dihydrodibenzoxepines, represented by AJ3941, was tested in animal models of global ischaemia and hypoxia, and found to be protective. AJ3941 is an inhibitor of lipid peroxidation (Kurakawa etal., 1991). A novel quinazoline fumarate (KB56666, was found to inhibit lipid peroxidation in rat brain homogenates and isolated mitochondria. In a rat focal stroke model, KE56666 prevented brain oedema and neuronal damage in the ischaemic zone (Hara etal., 1991). 

A series of 4,4-disubstituted quinazolin-2-ones derived from HTV nonnucleoside reverse transcriptase inhibitor leads have shown good in vitro potency and in vivo efficacy [28]. Using FLIPR assays on cell lines with different resting membrane potentials, TTA-Q3 (10) and TTA-Q6 (11)... 

Novel quinazoline derivatives like IC87114 (compound 15, Fig. 3) have been disclosed as inhibitors of pi 105 with good selectivity over the other... 

Quinazoline Template-Based Inhibitors AZM475271 (M475271) and AZD0530... 

Hypersensitivity to quinazolines (eg, doxazosin, prazosin, terazosin) moderate or severe hepatic insufficiency coadministration with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir). 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

An improved procedure for the selective alkylation of 2,4-quinazolinediones at the 1-position via the 2,4-bistri-methylsilyloxy derivatives has been developed <20030PD700>. This procedure enabled a large-scale synthesis of the aldose reductase inhibitor FK366 28 from the bistrimethylsilyloxy quinazoline 27 (Scheme 2). 

Another class of quinazoline antitumor agent under development is represented by ispinesib (SB 715992) 1162, a KSP kinesin inhibitor, which is being evaluated against head and neck cancer <2006MI627>. 

The ascaracide fenazaquin 1175 is active against several spider mite species, while DPC-083 (BMS 561390) 1176 is an anti-HIV reverse transcriptase inhibitor <2000JME2019>. The quinazoline 1177 has recently been identified as a lead compound for the development of selective inhibitors of lymphocyte-specific kinase (Lck) which is involved in T-cell-mediated autoimmune and inflammatory disease <2006JME5671>. 

Chemical Class Dihydrofolate reductase inhibitor substituted quinazoline Clinical Pharmacology ... 

A series of 6- and 7-aciylamide derivatives of 4-(phenylamino)-quinazoline and 4-(phenylainino)-pyridopyrimidine, classes of epidermal growth factor receptor (EGER) inhibitors, have been prepared from the corresponding amino compounds by reaction with actoyl chloride/base <99JMC1803>. Reaction of thionyl chloride with hexahydro-7-methyl-pyrimido[l,6-a]-pyrimidine-6,8-dione yields the corresponding 9,9 -thiobispyriiiudopyrimidine derivative <99JHC453>. 

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