A Facile Synthesis of <i>N</i>-Carbamoylamino Acids

Peptides U 0400A Facile Synthesis of N-Carbamoylamino Acids. -Alkylation of mono-N-substituted parabanic acids followed by hydrolysis of the dialkylated intermediate provides the required druglike urea products which represent peptide analogues. The products are obtained in good to excellent yields with high purity and the method can be applied to the preparation of combinatorial libraries. -(BOGOLUBSKY, A. V.; RYABUKHIN*, S. V.; PAKHOMOV, G. G.; OSTAPCHUK, E. N.; SHIVANYUK, A. N.; TOLMACHEV, A. A.; Synlett 2008, 15, 2279-2282; Enamine Ltd., Kiev 01103, Ukraine; Eng.) -Lindner 04-181

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ChemInform Abstract: A Facile Synthesis of N‐Carbamoylamino Acids.

Bogolubsky

Pakhomov

Ostapchuk

et al. 2009

ChemInform

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Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor

Huestis¹,

Cruz²,

DiPasquale³

et al. 2021

J. Med. Chem.

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Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

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A Facile Synthesis of N-Carbamoylamino Acids

Abstract: N-Carbamoylamino acids were obtained through the alkylation of monosubstituted parabanic acids followed by hydrolysis of the intermediate products. This new methodology furnishes structurally and functionally diverse N-carbamoylamino acids in high preparative yields and excellent purity.

Cited by 2 publications

References 7 publications

ChemInform Abstract: A Facile Synthesis of N‐Carbamoylamino Acids.

ChemInform Abstract: A Facile Synthesis of N‐Carbamoylamino Acids.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor

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