Solid phase synthesis of quinazolinones

Mayer, John P.; Lewis, George S.; Curtis, Michael J; Zhang, Jingwen

doi:10.1016/s0040-4039(97)10276-3

Cited by 95 publications

(47 citation statements)

References 13 publications

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“…Thus, more derivatives of C series were made ( Fig. 2B) in accordance with the method described previously (Mayer et al, 1997). Amino-substituted compound (C11) was obtained by reduction of its corresponding nitro substituted compound (C10).…”

Section: Resultsmentioning

confidence: 99%

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Pharmacological Characterization of a Novel Nonpeptide Antagonist for Formyl Peptide Receptor-Like 1

Zhou¹,

Zhang

Nanamori³

et al. 2007

Mol Pharmacol

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A series of quinazolinone derivatives were synthesized based on a hit compound identified from a high-throughput screening campaign targeting the human formyl peptide receptor-like 1 (FPRL1). Based on structure-activity relationship analysis, we found that substitution on the para position of the 2-phenyl group of the quinazolinone backbone could alter the pharmacological properties of the compound. The methoxyl substitution produced an agonist 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide (Quin-C1; C1), whereas a hydroxyl substitution resulted in a pure antagonist, Quin-C7 (C7). Several partial agonists were derived from other substitutions on the para position. C7 partially displaced3 H]N-formyl-Met-Leu-Phe to formyl peptide receptor. In functional assays using FPRL1-expressing RBL-2H3 cells, C7 inhibited calcium mobilization and chemotaxis induced by WKYMVm and C1 and degranulation elicited by C1. C7 also suppressed C1-induced extracellular signal-regulated kinase phosphorylation and reduced arachidonic acid-induced ear edema in mice. This study represents the first characterization of a nonpeptidic antagonist for FPRL1 and suggests the prospect of using low molecular weight compounds as modulators of chemoattractant receptors in vitro and in vivo.The human formyl peptide receptor (FPR) family of chemoattractant receptors consists of FPR, formyl peptide receptor-like 1 (FPRL1), and FPRL2. These receptors are expressed primarily in neutrophils and monocytes and exert important functions in inflammation and immunity (Le et al., 2002). The FPRL1 gene was initially cloned in 1992 for its homology with FPR cDNA (Bao et al., 1992;Murphy et al., 1992;Ye et al., 1992). The prototype of chemotactic peptide N-formyl-Met-Leu-Phe (fMLF), an agonist for FPR, can also activate FPRL1 with a reduced affinity (Quehenberger et al., 1993). Stimulation of FPRL1 elicits a cascade of host defense reactions against pathogens, including chemotaxis, superoxide generation, and exocytosis in human neutrophils. In addition, it was reported that FPRL1 attenuates HIV-1 infection by desensitizing and down-regulating the chemokine receptors CCR5 and CXCR4, which serve as major coreceptors for HIV-1, on monocyte surfaces (Li et al., 2001). A recent study showed that the expression of FPRL1 in mouse C26 cells markedly reduced tumorigenicity in syngeneic mice and resulted in high levels of humoral immune response to both FPRL1-containing and wild-type C26 cells . The data indicate that FPRL1 also plays a key role in specific antitumor response. The expression of FPRL1 in activated microglial cells and its function as a receptor for A␤(1-42), a 42-amino acid form of the ␤-amyloid peptide, suggest that FPRL1 is closely related to neurodegenerative disorders . Investigation in ligand binding, signal transduction, and functional properties of FPRL1 is expected to facilThis project was supported in part by grants from the Ministry

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Section: Resultsmentioning

confidence: 99%

“…The quinazolinone series compounds were synthesized according to the method described previously (Mayer et al, 1997), and the synthetic route is shown in Fig. 1.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of a Novel Nonpeptide Antagonist for Formyl Peptide Receptor-Like 1

Zhou¹,

Zhang

Nanamori³

et al. 2007

Mol Pharmacol

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“…The 2-substituted quinazolinones were obtained through the cyclization of anthranilhydrazine and aldehyde under acidic conditions. The synthesis route (Mayer et al, 1997) permits the introduction of a wide range of substituents into the 2-position of this ring system using different benzaldehydes. The structure of the original compound, based upon which Quin-C1 is synthesized, is shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

A Novel Nonpeptide Ligand for Formyl Peptide Receptor-Like 1

Nanamori¹,

Cheng²,

Mei³

et al. 2004

Mol Pharmacol

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Formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor that binds natural and synthetic peptides as well as lipoxin A 4 and mediates important biological functions. To facilitate its pharmacological characterization, we screened a compound library and identified a substituted quinazolinone (Quin-C1, 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide) as a ligand for FPRL1. Quin-C1 induces chemotaxis and secretion of ␤-glucuronidase in peripheral blood neutrophils with a potency of approximately 1/1000 of that of the peptide agonist WKYMVm. In studies using transfected rat basophilic leukemia (RBL) cell lines expressing either formyl peptide receptor or FPRL1, Quin-C1 induced enzyme release from RBL-FPRL1 but not RBL-FPR cells. Likewise, Quin-C1 selectively stimulates calcium mobilization in RBL-FPRL1 cells, a response that was markedly inhibited by pertussis toxin. Quin-C1 also stimulates phosphorylation of extracellular signal-regulated protein kinases 1 and 2 and induces internalization of an FPRL1 fused to green fluorescent protein. In degranulation assays, both the FPRL1-selective peptide agonist MMK1 and Quin-C1 exhibited lower efficacy and potency than WKYMVm, with EC 50 values of 7.17 ϫ 10 Ϫ8

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“…Compound 9 (3.07 g 0.1 mol)was added to 85% phosphoric acid (25 ml) at 180 o C. the reaction mixture was heated for 30 min then cooled and diluted with water 100 ml the solid was filtered and recrystallization from the proper solvent gave (10 …”

Section: -(34-dimethoxybenzylideneamino)-2-propylquinazolin-4(3h)-omentioning

confidence: 99%

Synthesis and Biological Evaluation of Some New2-propyl- 4(3H)-Quinazolinone Derivatives as Anti-bacteria

Eissa¹,

Elmetwally²,

El‐Hashash³

et al. 2008

Journal of the Korean Chemical Society

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Solid phase synthesis of quinazolinones

Cited by 95 publications

References 13 publications

Pharmacological Characterization of a Novel Nonpeptide Antagonist for Formyl Peptide Receptor-Like 1

Pharmacological Characterization of a Novel Nonpeptide Antagonist for Formyl Peptide Receptor-Like 1

A Novel Nonpeptide Ligand for Formyl Peptide Receptor-Like 1

Synthesis and Biological Evaluation of Some New2-propyl- 4(3H)-Quinazolinone Derivatives as Anti-bacteria

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