Synthesis and anticonvulsant activity of 2-iminohydantoins

Kwon, Chul‐Hoon; Iqbal, M.; Wurpel, John N.D.

doi:10.1021/jm00110a013

Cited by 34 publications

(17 citation statements)

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“…Chemistry In order to avoid handling highly polar and basic compounds as much as possible, we planned to perform the catalytic hydrogenation of guanidine 9 in the last stage, which was expected to construct iminoimidazolidinone framework, [7][8][9][10][11] as shown in Chart 1. Our synthesis started with installation of an acetic acid unit to commercially available 1.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 1-(4-Aminobutyl)-2-iminoimidazolidin-4-one Aimed at Preparation of a Creatinine-Specific Antibody

Moriya

Terayama

Hiramatsu

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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For the purpose of obtaining a creatinine-specific antibody, a creatinine derivative with 4-aminobutyl, which was served as a linker for preparing the creatinine-bovine serum albumin (BSA) conjugate, was synthesized from 4-benzylaminobutan-1-ol in 8 steps. Production of anti-creatinine antibodies was observed in two rabbits using the creatinine-BSA conjugate, although their titer was rather low.Key words creatinine derivative; synthesis; guanidinylation; anti-creatinine immunoglobulin Recently, we developed an immunochromatographic system for determination of the N 1 ,N 12 -diacetyl spermine (DiAcSpm) concentration in human urine 1) (Fig. 1). DiAcSpm is a newly developed tumor marker and is unique among existing tumor markers in that it is sensitive in detecting early cancers. 2,3)The immunochromatographic testing device can be used for personal health control and would eventually contribute to improvement in the efficiency of early detection of cancer, which is important for reducing the number of fatal cases of cancer. The quantity of daily excretion of urine components is usually estimated from arbitrarily excreted spot urine samples by creatinine normalization and is expressed in nmol substance per g creatinine. The validity of creatinine normalization in estimating daily DiAcSpm excretion in urine was in fact confirmed, 4) and creatinine-normalized DiAcSpm in urine has been shown to be a promising tumor marker as described above. To determine the quantity of creatinine-normalized DiAcSpm by immunochromatography, it is necessary to simultaneously determine the quantities of creatinine in urine samples. Yaffe's reaction, which utilizes the reaction of creatinine with picric acid to form orange-red-colored creatinine picrate in an alkaline solution, can be used for this purpose.5) However, substances in urine such as pyruvate, glucose, ascorbate, and billirubin are also known to form colored complexes and interfere with accurate determination of creatinine. An enzymatic method utilizing creatinine imidohydrolase and glutamate dehydrogenase is more accurate 6) but is not readily applicable to creatinine assays on a solid support that are run in parallel with the immunochromatographic determination of DiAcSpm. A creatinine-specific antibody, if available, would be readily applicable to immunochromatographic determination of creatinine. Moreover, DiAcSpm and creatinine could be determined on the same strip by using gold nanoparticles labeled with two antibodies. To obtain a creatinine-specific antibody, creatinine as a hapten must be conjugated to an appropriate carrier macromolecule. With this in mind, we designed a creatinine derivative (10) with 4-aminobutyl.

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Section: Resultsmentioning

confidence: 99%

Synthesis of 1-(4-Aminobutyl)-2-iminoimidazolidin-4-one Aimed at Preparation of a Creatinine-Specific Antibody

Moriya

Terayama

Hiramatsu

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…In the development of several drugs such as cimetidine, a analogous bioisosteric substitution has been successful. CNG-DPH was synthesized in 1970, 14 but no detailed study on the pharmacology or the pharmacokinetics has been performed.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] Fosphenytoin (ACC-9653) 10 is currently under clinical investigation for the treatment of the status epilepticus. 11 As an alternative approach, structural analogues of phenytoin such as 5,5-diphenyl-2-thiohydantoin, 12 4,4-diphenyl-1,2,5-thiazolidin-3-one 1,1-dioxide, 13 and 5,5-diphenyl-2-iminohydantoin 14 have been prepared but showed only a low anticonvulsant activity in animal models if any activity was noted at all. However, several 1-carbobenzoxy derivatives of 5,5-diphenyl-2-iminohydantoin showed good activity in the MES test.…”

Section: Introductionmentioning

confidence: 99%

“…However, several 1-carbobenzoxy derivatives of 5,5-diphenyl-2-iminohydantoin showed good activity in the MES test. 14 These observations led us to investigate if the introduction of an electron-withdrawing cyano group could restore the anticonvulsant activity and, moreover, improve the bioavailability of the compound in comparison to phenytoin.…”

Section: Introductionmentioning

confidence: 99%

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Bioavailability and Anticonvulsant Activity of 2-Cyanoguanidinophenytoin, a Structural Analogue of Phenytoin

Lambert

Masereel

Gallez

et al. 1996

Journal of Pharmaceutical Sciences

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0 Phenytoin is extensively used in Europe and the United States for the treatment of generalized tonic clonic seizures (grand mal). However, the efficacy is lowered by the erratic bioavailability after oral administration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsant activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogue of phenytoin, which was obtained by the replacement of the urea moiety by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneous Biltz conditions and under heterogeneous phase-transfer conditions. CNG-DPH is poorly water soluble and has a pK a of 5.3. At pH 7.4, log P′ was 1.16, from which a pH-independent log P of 3 can be calculated. Pharmacokinetic parameters were obtained after oral administration of CNG-DPH to rats and were compared to those of phenytoin after administration of an equimolar amount. AUC, t max , and C max were significantly increased compared to those of phenytoin. The anticonvulsant profile was similar to the profile of phenytoin. CNG-DPH was active in the maximal electroshock seizure test, albeit 7-fold less active than phenytoin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methylaspartate, strychnine, and bicuculline. It is concluded that while the bioisosteric exchange of the urea moiety of the molecule with the cyanoguanidine moiety dramatically changed the physicochemical and pharmacokinetic parameters compared to those of phenytoin, the concomitant change of the affinity toward molecular targets reduced the pharmacological activity and the therapeutic efficacy of the compound.

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“…In general, at least one aromatic group, e.g., phenyl or thienyl, is essential for the anticonvulsant activity of the hydantoins [Kupferberg, 1995]. However, the structure-activity relationship (SAR) of 2-iminohydantoins was found to be quite differ-ent from that of hydantoins [Kwon et al, 1991;Sun et al, 1994]. However, the structure-activity relationship (SAR) of 2-iminohydantoins was found to be quite differ-ent from that of hydantoins [Kwon et al, 1991;Sun et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

1999

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A series of (S)-(+)-5-n-propyl-2-iminohydantoins with various N-1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure-activity relationship (SAR) of 2-iminohydantoins. Compounds with N-1 phenoxycarbonyl (2), ethoxycarbonyl (6), t-butoxycarbonyl (7), propoxycarbonyl (12), and p-methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED 50 values in the range of 72-124 mg/kg. All of the above compounds except 7 also showed activity against the pentylenetetrazol (PTZ) test with ED 50 values in the range of 65-178 mg/kg. Compound 6 provided the highest protective index (PI) value against the PTZ test, while 7 provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six-member ring (4) destroyed the activity. In addition, N-1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N-1 oxycarbonyl sidechain in the 2iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17-26, 1999.

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Synthesis and anticonvulsant activity of 2-iminohydantoins

Cited by 34 publications

References 0 publications

Synthesis of 1-(4-Aminobutyl)-2-iminoimidazolidin-4-one Aimed at Preparation of a Creatinine-Specific Antibody

Synthesis of 1-(4-Aminobutyl)-2-iminoimidazolidin-4-one Aimed at Preparation of a Creatinine-Specific Antibody

Bioavailability and Anticonvulsant Activity of 2-Cyanoguanidinophenytoin, a Structural Analogue of Phenytoin

Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

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