Synthesis and biological evaluation of optically active Ki16425.
An enantionselective synthesis of both enantiomers of Ki16425, which possesses selective LPA antagonistic activity, was achieved. The isoxazole core was constructed by a 1,3-dipolar cycloaddition of nitrile oxide with alkyne and condensation with the optically active α-phenethyl alcohol segment, which was prepared by an enantioselective reduction of arylmethylketone. Biological evaluation of both enantiomers of Ki16425 revealed that the (R)-isomer showed much higher antagonistic activity for LPA(1) and LPA(3) receptors.
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Takanao
T
Sato
Kenji
K
Sugimoto
Asuka
A
Inoue
Shinichi
S
Okudaira
Junken
J
Aoki
Hidetoshi
H
Tokuyama
D000480:Alkynes / Q000737:chemistry; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D000480:Alkynes; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid