1203306-05-1Relevant articles and documents
Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators
Le, Hoang V.,Hawker, Dustin D.,Wu, Rui,Doud, Emma,Widom, Julia,Sanishvili, Ruslan,Liu, Dali,Kelleher, Neil L.,Silverman, Richard B.
, p. 4525 - 4533 (2015)
Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S......O=C interaction with Glu-270, thereby inactivating the enzyme. (Figure Presented).
Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides
Connon, Stephen J.,Craig, Ryan,Smith, Simon N.
supporting information, p. 13378 - 13382 (2020/10/02)
The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation–cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.
PYRAZOLO-PYRIMIDIN-AMINO-CYCLOALKYL COMPOUNDS AND THEIR THERAPEUTIC USES
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Paragraph 0529, (2019/12/28)
Disclosed herein are pyrazolo-pyrimid in-ami no-cycloalkyl compounds, analogs thereof, pharmaceutical compositions comprising thereof and therapeutic uses therefor.
Enhanced enzymatic synthesis of the enantiopure intermediate for the blockbuster drug intermediate abacavir through a two-step enzymatic cascade reaction
Galla, Zsolt,Forró, Enik?,Fül?p, Ferenc
, p. 729 - 731 (2016/08/01)
A very efficient enzymatic two-step cascade reaction was devised (E?>?200) for the resolution of activated γ-lactams (±)-1 and (±)-2. The N-hydroxymethyl group worked as a traceless activating group, when the reactions were performed with H2O (0.5?equiv) in the presence of benzylamine (1?equiv) in i-Pr2O at 60?°C. The ring-opened enantiomerically pure γ-amino acids (1S,4R)-6 (ee?=?99%, intermediate of abacavir) and (1S,3R)-8 (ee?=?99%) and unreacted lactams (1S,4R)-1 and (1R,4S)-2 (ee???96%) were obtained in good yields (?43%). Treatment of (1S,4R)-1 and (1R,4S)-2 with 18% HCl or NH4OH resulted in (1R,4S)-6·HCl and (1S,3R)-8·HCl or (1S,4R)-3 and (1R,4S)-4 quantitatively, with ee???96%.
TETRAHYDROTHIOPHENE-BASED GABA AMINOTRANSFERASE INACTIVATORS
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, (2016/09/26)
Tetrahydrothiophene and related heterocyclic analogs and related methods for GABA aminotransferase inactivation.
1,3-DISUBSTITUTED CYCLOPENTANE DERIVATIVES
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Page/Page column 58; 59, (2015/02/25)
Compounds of the formula (I) in which R, Y, R1, X1, X2, X3 and q have the meanings indicated in Claim 1, are inhibitors of fatty acid synthase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.
Synthesis of cyclic γ-amino acids for foldamers and peptide nanotubes
Rodriguez-Vazquez, Nuria,Salzinger, Stephan,Silva, Luis F.,Amorin, Manuel,Granja, Juan R.
, p. 3477 - 3493 (2013/07/11)
Cyclic γ-amino acids are molecular building blocks of great interest in peptide and foldamer chemistry, as they allow the preparation of new structures that are not found in Nature. In this paper, we describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This arrangement, in most cases, induces the resulting peptides to adopt a flat conformation, which makes them appropriate for the design of foldamers that adopt β-sheet-type structures. We describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This makes them suitable for the design of foldamers that adopt β-sheet-type structures.
Inhibitors of protein kinases
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, (2011/10/04)
Compounds of general Formula (I): wherein R1, R2, R3, Ra, A, B and x are as defined herein are inhibitors of protein kinases in particular members of the cyclin-dependent kinase family and/or the glycogen synthase kinase 3 family and are useful in preventing and/or treating any type of pain, inflammatory disorders, cancer, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases, metabolic disorders, renal diseases, neurologic and neuropsychiatric diseases and neurodegenerative diseases.
Enzymatic method for the synthesis of blockbuster drug intermediates - Synthesis of five-membered cyclic γ-amino acid and γ-lactam enantiomers
Forro, Eniko,Fueloep, Ferenc
experimental part, p. 5263 - 5268 (2009/06/18)
A very efficient enzymatic method was developed for the synthesis of cyclic γ-lactam and γ-amino acid enantiomers, intermediates for drugs with a prominent turnover (e.g., abacavir and carbovir), through the CAL-B-catalysed enantioselective (E > 200) hydrolysis of the corresponding N-Boc protected and unprotected racemic γ-lactams with H2O in iPr2O. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
Methyl-blocked dimeric α,γ-peptide nanotube segments: Formation of a peptide heterodimer through backbone-backbone interactions
Brea, Roberto J.,Amorin, Manuel,Castedo, Luis,Granja, Juan R.
, p. 5710 - 5713 (2007/10/03)
Cyclic peptides can dimerize through β-sheet-like hydrogen bonding. Heterodimerization is favored over homodimerization, which creates interesting combinatorial possibilities without detriment to the functionalization of amino acid side chains. These dime
