134176-18-4Relevant academic research and scientific papers
Design, synthesis, and pharmacological characterization of (+)-2- aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): A potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties
Monn, James A.,Valli, Matthew J.,Massey, Steven M.,Wright, Rebecca A.,Salhoff, Craig R.,Johnson, Bryan G.,Howe, Trevor,Alt, Charles A.,Rhodes, Gary A.,Robey, Roger L.,Griffey, Kelly R.,Tizzano, Joseph P.,Kallman, Mary J.,Helton, David R.,Schoepp, Darryle D.
, p. 528 - 537 (1997)
2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (τ1 and τ2) which determine the relative positions of the α- amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9°or 202°and τ2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)- 9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 μM. Importantly, the mGluR agonist effects of (+)- 9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.
Novel asymmetric synthesis of a bicyclo[3.1.0]hexane derivative by an efficient retro-Diels-Alder strategy
Moher, Eric D.
, p. 8637 - 8640 (1996)
The first preparation of enantiomerically pure bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester (1), a valuable synthetic intermediate, is described. The synthesis features a retro-Diels-Alder reaction as a key step. Conditions which allow for a high yielding thermal conversion of 3 to 4 are described.
C3′-cis-Substituted carboxycyclopropyl glycines as metabotropic glutamate 2/3 receptor agonists: Synthesis and SAR studies
González, Rosario,Collado, Iván,López De Uralde, Beatriz,Marcos, Alicia,Martín-Cabrejas, Luisa M.,Pedregal, Concepción,Blanco-Urgoiti, Jaime,Pérez-Castells, Javier,Fernández, M. Alejandro,Andis, Sherri L.,Johnson, Bryan G.,Wright, Rebecca A.,Schoepp, Darryle D.,Monn, James A.
, p. 6556 - 6570 (2005)
The synthesis of a series of C3′-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is repo
TMG catalyzed cyclopropanation of cyclopentenone. Illustration by a simple synthesis of bicyclo[3.1.0]hexane-2-one derivatives
Zhang, Fuyao,Moher, Eric D.,Zhang, Tony Y.
, p. 3277 - 3279 (2007)
The catalytic preparation of bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester 1 is described by cyclopropanation of cyclopentenone using 1,1,3,3-tetramethylguanidine (TMG) as a catalyst in high yield and high diastereoselectivity. This process has been applied to an efficient synthesis of the important intermediate, β-hydroxyl cyclopentanone 2.
Stereoselective cyclopropanation of enones with ethyl dimethylsulfonium acetate bromide in the presence of DBU
Collado, Ivan,Dominguez, Carmen,Ezquerra, Jesus,Pedregal, Concepcion,Monn, James A.
, p. 2133 - 2136 (1997)
The cyclopropanation reaction of α, β-unsaturated ketones 1a-c with ethyl (dimethyl sulfuranylidene) acetate (EDSA), generated in situ from the corresponding sulfonium bromide salt and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in toluene, leads exclusively to the exo adduct 2a-c (d.e. = 100%). Acyclic enones 1d-g, give mainly the 'trans' cyclopropanes 4d-g with a high degree of stereocontrol (d.e. 380%). Changing the solvent to CHCl3 affords a 2:1 mixture of 'trans' and 'cis' cyclopropanes 4d-g and 5d-g respectively. The 'cis' isomers 5d-g can be epimerizated to the alternative 'trans' isomers 6d-g under basic conditions.
Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase
Colombo, Cinzia,Podlipnik, ?rtomir,Presti, Leonardo Lo,Niikura, Masahiro,Bennet, Andrew J.,Bernardi, Anna
, (2018)
The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; siali-dase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.
Process development of (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (LSN344309)
Rasmy, Ossama M.,Vaid, Radhe K.,Semo, Michael J.,Chelius, Erik C.,Robey, Roger L.,Alt, Charles A.,Rhodes, Gary A.,Vicenzi, Jeffery T.
, p. 28 - 32 (2006)
Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Buecherer-Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-α- methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.
ISOXAZOLE CARBOXYLIC ACIDS AS LPA ANTAGONISTS
-
Page/Page column 91-92, (2021/01/22)
The present invention provides compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
TRIAZOLE CARBOXYLIC ACIDS AS LPA ANTAGONISTS
-
Page/Page column 96, (2021/01/22)
The present invention provides compounds of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
PRODRUG OF AMINO ACID DERIVATIVE
-
Paragraph 0181, (2017/11/14)
Provided is an amino acid derivative prodrug represented by general formula (I-A) that is a prodrug form of an amino acid derivative which is a group 2 metabotropic glutamate receptor antagonist, or a pharmaceutically acceptable salt thereof. More specifically, provided is an amino acid derivative prodrug represented by general formula (I-A) that is a preventive or therapeutic drug for mood disorders (including depression and bipolar disorder), anxiety disorder, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscular rigidity, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, brain infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorders, head trauma, inflammation and immune- related diseases, and so on.
