625386-10-9Relevant articles and documents
SELECTIVE FOXO INHIBITORS FOR TREATMENT OF DIABETES AND OTHER DISORDERS RELATED TO IMPAIRED PANCREATIC FUNCTION
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Paragraph 0121-0122, (2020/10/18)
Various embodiments relate to a compound (represented by Formula I) or a pharmaceutically acceptable salt or tautomer thereof. The compound may selectively inhibit a Forkhead Box O1 (FOXO1) transcription factor. Various embodiments relate to methods compr
Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors
Sun, Shaoyi,Zhang, Zaihui,Pokrovskaia, Natalia,Chowdhury, Sultan,Jia, Qi,Chang, Elaine,Khakh, Kuldip,Kwan, Rainbow,McLaren, David G.,Radomski, Chris C.,Ratkay, Leslie G.,Fu, Jianmin,Dales, Natalie A.,Winther, Michael D.
, p. 455 - 465 (2015/01/30)
Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100 mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
PYRAZOLE DERIVATIVES WHICH MODULATE STEAROYL-COA DESATURASE
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Page/Page column 69, (2011/04/25)
The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivative
New heterocyclic β-sheet ligands with peptidic recognition elements
Rzepecki,Gallmeier,Geib,Cernovska, Katarina,Koenig,Schrader
, p. 5168 - 5178 (2007/10/03)
A detailed and comprehensive overview is presented about the design, modeling, and synthesis, as well as spectroscopic characterization, of a new class of β-sheet ligands. The characteristic feature of these compounds is a peptidic chimeric structure formed from a specific combination of aminopyrazolecarboxylic acids with naturally occurring α-amino acids. These hybrid peptides are designed with the aid of molecular modeling to exist mainly in an extended conformation. All their hydrogen bond donors and acceptors can be aligned at the bottom face in such a way that a perfect complementarity toward β-sheets is obtained. Thus the aminopyrazoles impart rigidity and a highly efficient DAD sequence for the recognition of whole dipeptide fragments, whereas the natural α-amino acids are designed to mimick recognition sites in proteins, ultimately leading to sequence-selective protein recognition. The synthetic protocols either rely upon solution phase peptide coupling with a PMB protecting group strategy or solid-phase peptide coupling based on the Fmoc strategy, using the same protecting group. In solution, a key building block was prepared by catalytic reduction of a nitropyrazolecarboxylic acid precursor. Subsequently, it was (N-1)-protected with a PMB group, and elongated by HCTU- or T3P-assisted peptide coupling with dipeptide fragments, followed by PyClop-assisted coupling with another nitropyrazolecarboxylic acid building block. Final simultaneous deprotection of all PMB groups with hot TFA completed the high-yield protocol, which works racemization-free. After preparing a similar key building block with an Fmoc protection at N-3, we developed a strategy suitable for automated synthesis of larger hybrid ligands on a peptide synthesizer. Attachment of the first amino acid to a polystyrene resin over the Sieber amide linker is followed by an iterative sequence consisting of Fmoc deprotection with piperidine and subsequent coupling with natural α-amino acid via HATU/HOAt. High yields of free hybrid peptides are obtained after mild acidic cleavage from the resin, followed by deprotection of the PMB groups with hot TFA. The new aminopyrazole peptide hybrid compounds were characterized by various spectroscopic measurements including CD spectra, VT, and ROESY NMR experiments. All these accumulated data indicate the absence of any intramolecular hydrogen bonds and strongly support an extended conformation in solution, ideal for docking on to solvent-exposed β-sheets in proteins. Initial results from aggregation tests of pathological proteins with these and related ligands look extremely promising.
Aminopyrazole oligomers for β-sheet stabilization of peptides
Rzepecki,Wehner,Molt,Zadmard,Harms,Schrader
, p. 1815 - 1826 (2007/10/03)
A general concept for the stabilization of β-sheets by designed artificial ligands is introduced. The ligands have two key features: they contain acylated 3-aminopyrazoles with a DAD hydrogen bond donor and acceptor pattern, and they were synthesized as o
