Synthesis and Structure–Activity Relationship of Diarylamide Derivatives as Selective Inhibitors of the Proliferation of Human Endothelial Cells

Ogita, Haruhisa; Isobe, Yoshiaki; Takaku, Haruo; Sekine, Rena; Goto, Yuhei; Misawa, S.; Hayashi, Hideya

doi:10.1016/s0968-0896(02)00258-4

Cited by 23 publications

(8 citation statements)

References 12 publications

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“…But in the case of 2a and 2b, no substitution at X position, 3,4,5-trimethoxyphenyl substitution at the urea moiety enhanced the inhibitory activity and the selectivity as reported previ- ously. 8) So, the further modification was conducted based on 2d. Table 2 presents the result of the SAR study on the substituents at the urea moiety with the ethylene substitution at X position.…”

Section: Resultsmentioning

confidence: 99%

“…Table 2 presents the result of the SAR study on the substituents at the urea moiety with the ethylene substitution at X position. Considering the result of 2a and 2b, 8) we evaluated 2g that had the 3,4,5-trimethoxyphenyl group at the urea moiety like 2b. But in this case, contrary to our expectation, the trimethoxyphenyl substitution resulted in decreased the activity.…”

Section: Resultsmentioning

confidence: 99%

“…The condensation of 3 8) with corresponding acid halides was performed in the presence of triethylamine to provide 4a-c. Acid halide 10 was prepared from 9 with thionyl chloride, which was obtained by the condensation of 8 with ethyl bromoacetate followed by basic hydrolysis.…”

Section: Chemistrymentioning

confidence: 99%

“…In order to find more potent inhibitor, we also reported that the introduction of a ureido group to the B ring of our diarylamide derivatives make the inhibitory activity more potent and keep the selectivity for SMCs and 2b showed the most potent inhibitory activity for SMCs (IC 50 = 40 nM), which was 20-and 600-fold stronger than 1a and Tranilast respectively. 8) On the basis of these results (Fig. 1), we tried to confirm the effect of the linker between these rings against the proliferation of SMCs.…”

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Synthesis of Potent and Selective Inhibitors against the Proliferation of Human Coronary Artery Smooth Muscle Cells.

Ogita

Isobe

Takaku

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Proliferation of smooth muscle cells (SMCs) plays an important role in restenosis and in progression of atherosclerosis.2) Tranilast has been shown to inhibit platelet-derived growth factor (PDGF)-induced migration and proliferation in both SMCs 3) and endothelial cells (ECs). And the multicenter, randomized, double-blinded placebo-controlled trials demonstrated the potent preventive effect on restenosis after percutaneous transluminal coronary angioplasty (PTCA) in Japanese patients. 4,5) [at the phase III trial, 5) restenosis rate 18.8% (Tranilast 600 mg/d for 3 months, nϭ112) versus 44.1% (placebo, nϭ127); pϭ0.00005] But some patients had suffered liver dysfunction in these trials. We speculated that these frequent and severe side effects in these trials might have been caused by the high dose of Tranilast. In addition, the selective inhibitors of the proliferation of SMCs over that of ECs was more preferable for the treatment of restenosis than the non-selective inhibitors like Tranilast.6) So, we had been trying to search more potent and SMCs-selective compounds by modification of Tranilast.We previously reported a series of diarylamide derivatives, exhibiting potent and highly selective inhibition against SMCs proliferation induced by PDGF-BB. 7) We conducted that structure-activity relationship (SAR) study of the substituents at the A and B rings, and found potent inhibitor, 1a, which had about 30-fold stronger activity than Tranilast. In that case, the linker between A and B rings was not so influenced on the inhibitory activities (1a-c). In order to find more potent inhibitor, we also reported that the introduction of a ureido group to the B ring of our diarylamide derivatives make the inhibitory activity more potent and keep the selectivity for SMCs and 2b showed the most potent inhibitory activity for SMCs (IC 50 = 40 nM), which was 20-and 600-fold stronger than 1a and Tranilast respectively. 8) On the basis of these results (Fig. 1), we tried to confirm the effect of the linker between these rings against the proliferation of SMCs. In this paper, we report the results of the further modification of these urea derivatives. ChemistryThe syntheses of desired urea derivatives 2c-s are outlined in Chart 1. The condensation of 3 8) with corresponding acid halides was performed in the presence of triethylamine to provide 4a-c. Acid halide 10 was prepared from 9 with thionyl chloride, which was obtained by the condensation of 8 with ethyl bromoacetate followed by basic hydrolysis. Then, catalytic hydrogenation, followed by the condensation of 5a-c with the corresponding isocyanates gave the desired urea derivatives 2c-s. Compound 2e was obtained by the condensation of 3 with 7 by using 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP) 9,10) as a condensation reagent. BiologyA series of these compounds were evaluated for their inhibitory activities on PDGF-induced proliferation of human coronary artery SMCs and fetal bovine serum (FBS)-induced the proliferation of human coronary artery ECs. Inhibit...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis of Potent and Selective Inhibitors against the Proliferation of Human Coronary Artery Smooth Muscle Cells.

Ogita

Isobe

Takaku

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…One example is in a type of HIV protease inhibitor [143]. A drug known as Tranilast, N-(3,4-dimethoxycinnamoyl)-AA, an avenanthramide (see 2.1.3), was originally developed as an anti-allergy drug but it has since been shown to inhibit angiogenesis [144], an important phenomenon in cancer and other degenerative deceases. Very recently pyridine analogues of flufenamic acid (27) have been evaluated as anti cancer agents [145].…”

Section: Alkaloids Derived From Anthranilic Acidmentioning

confidence: 99%

The Chemistry of Anthranilic Acid

Wiklund¹,

Bergman

2006

COS

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Mild Palladium‐Catalyzed Oxidative Direct ortho‐CH Acylation of Anilides under Aqueous Conditions

et al. 2013

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Palladium-catalyzed cross-dehydrogenative coupling between anilides and aromatic aldehydes was achieved under aqueous conditions. A wide variety of the desired benzophenone derivatives was isolated in good to excellent yield. The reaction rate acceleration effect of acid and detergent has been demonstrated. Mechanistic insight has been obtained from quantum chemical calculations.Transition metal-catalyzed direct C À H bond functionalization is one of the most important transformations in recent organic synthetic strategies. [1] Although catalytic transformations based on palladium catalysts are the most frequently utilized oxidative coupling methods in organic syntheses, these reactions usually require harsh conditions (high temperature, long reaction time, necessity of inert atmosphere). Therefore the development of efficient palladium-catalyzed oxidative couplings based on highly active catalyst systems under mild reaction conditions is still highly demanded. Regarding the mechanisms of palladium-catalyzed transformations the presence of monometallic palladium complexes in the catalytic cycle is well accepted. [2] However, very recently the special role and activity of bimetallic palladium species has been discovered and demonstrated in several coupling reactions involving a C À H functionalization step. [3] Be-sides the assessment of the synthetic potential of bimetallic complexes in organic chemistry, a thorough understanding of their working mechanism is also essential. [4] There are several applications of palladium-catalyzed oxidative transformations for the formation of new carbon-carbon bonds via functional group-directed ortho-substitution. [5] Very recently, the synthesis of aromatic ketones from phenylpyridines [6] or acetanilides [7] could be achieved by the palladium-catalyzed oxidative coupling of aldehydes [8] including a C À H activation step.The recently described methodologies of Zhou, [7a] Kwong [7b] and Yu [7c] enable the transformation in toluene at 120 8C, 90 8C, and 40 8C, respectively (Scheme 1.). The latter procedure provides the most efficient conditions for the desired coupling due to the relatively short reaction time under the applied conditions (40 8C, 3 h). Utilization of ketocarboxylic acids instead of aldehydes enables the formation of benzophenone derivatives in a similar palladium-catalyzed coupling at room temperature as it was demonstrated by Ge and co-workers. [9] This transformation works efficiently at room temperature and it has excellent functional group tolerance.It is of note, amongst the previous methodologies depicted on Scheme 1., that only Kwongs proce-A C H T U N G T R E N N U N G dure [7b] offers possibilities for the transformation of ortho-substituted acetanilides.Palladium-catalyzed oxidative coupling of acetanilides with aromatic aldehydes results in 2-acylacetanilides and 2-aminobenzophenone derivatives after hydrolytic cleavage of the amide bond, which are impor-

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Synthesis and Structure–Activity Relationship of Diarylamide Derivatives as Selective Inhibitors of the Proliferation of Human Endothelial Cells

Cited by 23 publications

References 12 publications

Synthesis of Potent and Selective Inhibitors against the Proliferation of Human Coronary Artery Smooth Muscle Cells.

Synthesis of Potent and Selective Inhibitors against the Proliferation of Human Coronary Artery Smooth Muscle Cells.

The Chemistry of Anthranilic Acid

Mild Palladium‐Catalyzed Oxidative Direct ortho‐CH Acylation of Anilides under Aqueous Conditions

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