Synthesis and Biological Activity of (S)-2-Amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic Acid (TAN-950 A) Derivatives

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概要

• 論文の詳細を見る

• (S)-2-Amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a-o, 15a-o were investigated. Optically active TAN-950 A analogs 15a-h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16,prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j-o, respectively, utilizing a similar sequence of reactions.Most of TAN-950 A derivatives 6a-o, 15a-o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d-g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activiting effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. The most potent and selective NMDA agonistic activity was observed with (R)-3-methyl-nor-TAN-950 A (15m).

• 公益社団法人日本薬学会の論文
• 1991-05-25

著者

• 岸本 彰二

  Pharmaceutical Research Laboratories Iii Takeda Chemical Industries Ltd.

• 岸本 彰二

  Chemistry Research Laboratories, Takeda Chemical Industries, Ltd.

• 岸本 彰二

  Pharmaceutical Research Laboratories Iii Pharmaceutical Research Division Takeda Chemical Industries

• Itoh K

  Medicinal Chemistiy Research Laboratories I Pharmaceutical Research Division Takeda Chemical Industr

• Itoh K

  Pharmaceutical Research Laboratories Iii Pharmaceutical Research Division Takeda Chemical Industries

• Tamura N

  Pharmaceutical Research Laboratories Iii Pharmaceutical Research Division Takeda Chemical Industries

• 田村 典一

  武田薬品工業(株)

• Tamura N

  Medicinal Chemistry Laboratories Pharmaceutical Research Division Takeda Chemical Industries Ltd.

• 田村 典一

  Chemistry Research Laboratories Research and Development Division, Takeda Chemical Industries, Ltd.,

• 松下 義弘

  Chemistry Research Laboratories Research and Development Division, Takeda Chemical Industries, Ltd.,

• 岩間 斗史

  Biology Research Laboratories Research and Development Division, Takeda Chemical Industries, Ltd.,

• 原田 節夫

  Microbiology Research Laboratories Research and Development Division, Takeda Chemical Industries, Lt

• 伊藤 克己

  Chemistry Research Laboratories Research and Development Division, Takeda Chemical Industries, Ltd.,

• 原田 節夫

  Microbiology Research Laboratories Research And Development Division Takeda Chemical Industries Ltd.

• Itoh Kinuyo

  Department Of Materials Chemistry & Frontier Research Center Graduate School Of Engineering. Osa

• Itoh Kunihiko

  Dept. Pharmaceutical Sciences Akita University

• Tamura N

  Takeda Chemical Ind. Ltd. Osaka Jpn

• Matsushita Y

  Pharmaceutical Research Division Takeda Chemical Industries Ltd.

• 岩間 斗史

  Biology Research Laboratories Research And Development Division Takeda Chemical Industries Ltd.

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