191471-72-4Relevant articles and documents
Process development for a key synthetic intermediate of LY2140023, a clinical candidate for the treatment of schizophrenia
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
, p. 1266 - 1274 (2011)
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.
The synthesis of isotopically labeled (+)-2-amino-bicyclo[3.1.0]hexane-2,6- carboxylic acid and its 2-oxa-and 2-thia-analogs
Wheeler, William J.,O'Bannon, Douglas D.,Kennedy, Joseph H.,Monn, James A.,Tharp-Taylor, Roger W.,Valli, Matthew J.,Kuo, Fengjiun
, p. 605 - 620 (2007/10/03)
As part of a program aimed at the design of conformationally constrained analogs of glutamic acid, (+)-2-aminobicyclo[3.1.0]hexane-2,6-carboxylic acid (1), identified as a highly potent, selective, group II metabotropic glutamate receptor agonist has been synthesized and studied clinically. Heterocyclic analogs of 1 were subsequently synthesized in which the C-2 methylene has been replaced by an oxygen atom (2) or a sulfur atom (3). C-14 labeled isotopomers of 1, 2 and 3 have been synthesized to facilitate pre-clinical ADME studies. A tritium labeled isotopomer of 1 was also synthesized for use in in vitro experiments. A stable labeled isotopomer of rac-1 was prepared for use as an internal standard for bioanalytical assays. The key step in each of these syntheses was the reaction of chiral ketone 4, 5 or 6 with K14CN/ (NH4)2CO3 using the Bucherer-Berg protocol. In the preparation of the stable labeled isotopomer, rac-4-[13C 2] was prepared in two steps from ethyl bromoacetate-[UL- 13C2]; subsequent reaction of rac-4-[13C 2] with K13CN/15NH4Cl/Na 2CO3, followed by hydrolysis of the hydantoin yielded rac-1-[13C3, 15N]. Copyright
Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid (LY354740): Identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors
Monn, James A.,Valli, Matthew J.,Massey, Steven M.,Hansen, Marvin M.,Kress, Thomas J.,Wepsiec, James P.,Harkness, Allen R.,Grutsch Jr., John L.,Wright, Rebecca A.,Johnson, Bryan G.,Andis, Sherri L.,Kingston, Ann,Tomlinson, Rosemarie,Lewis, Richard,Griffey, Kelly R.,Tizzano, Joseph P.,Schoepp, Darryle D.
, p. 1027 - 1040 (2007/10/03)
As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6- dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane- 4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (- )-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 ± 4 and 8.4 ± 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, K(i) = 14.1 ± 1.4 nM at mGlu2 and 5.8 ± 0.64 nM at mGlu3; (-)-10, K(i) = 40.6 ± 3.7 nM at mGlu2 and 4.7 ± 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 ± 0.26 nM at mGlu2 and 4.58 ± 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 ± 0.81 nM at mGlu2 and 7.63 ± 2.08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 ± 46 nM) and at micromolar concentrations (EC50 = 2 430 ± 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 ± 130 and 7 340 ± 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.
