Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist.
In this paper, we describe the synthesis of (+)-(1R( *),2R( *))-2-[(1S( *))-1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid (+)-16a, a compound, that is, fluorinated at the alpha position of the carboxylic acid in the cyclopropane ring of a group II mGluRs antagonist, 1 (LY341495), using a previously reported stereoselective cyclopropanation reaction. The fluorinated compound (+)-16a exhibited almost the same affinity (IC(50)=3.49 nM) for mGluR2 as 1 but had a superior pharmacokinetic profile. Furthermore, a marked elevation of the plasma levels of (+)-16a was observed following the administration of a prodrug, (+)-17.
Sakagami
Kazunari
K
Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama-shi, Saitama 331-9530, Japan. kazunari.sakagami@po.rd.taisho.co.jp
Yasuhara
Akito
A
Chaki
Shigeyuki
S
Yoshikawa
Ryoko
R
Kawakita
Yasunori
Y
Saito
Akio
A
Taguchi
Takeo
T
Nakazato
Atsuro
A
D000818:Animals; D018360:Crystallography, X-Ray; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C528984:2-(1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl)-1-fluorocyclopropanecarboxylic acid, 6-heptyl ester; C528983:2-(1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl)-1-fluorocyclopropanecarboxylic acid; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2