- Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: Identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors
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(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,25-2- carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonists in cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, to mGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11 with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 in rats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonist potency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulations in a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.
- Monn, James A.,Massey, Steven M.,Valli, Matthew J.,Henry, Steven S.,Stephenson, Gregory A.,Bures, Mark,Hérin, Marc,Catlow, John,Giera, Deborah,Wright, Rebecca A.,Johnson, Bryan G.,Andis, Sherri L.,Kingston, Ann,Schoepp, Darryle D.
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- Process development for a key synthetic intermediate of LY2140023, a clinical candidate for the treatment of schizophrenia
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To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer-Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.
- Waser, Mario,Moher, Eric D.,Borders, Sandy S. K.,Hansen, Marvin M.,Hoard, David W.,Laurila, Michael E.,Letourneau, Michael E.,Miller, Richard D.,Phillips, Michael L.,Sullivan, Kevin A.,Ward, Jeffrey A.,Xie, Chaoyu,Bye, Cheryl A.,Leitner, Tanja,Herzog-Krimbacher, Brigitte,Kordian, Marcus,Muellner, Martin
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experimental part
p. 1266 - 1274
(2012/01/06)
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- PRODRUGS OF EXCITATORY AMINO ACIDS
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This invention relates to synthetic excitatory amino acid prodrugs and processes for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorder
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