152120-62-2Relevant articles and documents
Application of the guanidine-acylguanidine bioisosteric approach to argininamide-type NPY Y2 receptor antagonists
Pluym, Nikola,Brennauer, Albert,Keller, Max,Ziemek, Ralf,Pop, Nathalie,Bernhardt, Guenther,Buschauer, Armin
scheme or table, p. 1727 - 1738 (2012/01/14)
Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptideY (NPY) Y2 receptor (Y2R) antagonists related to BIIE0246 were synthesized. Starting from ornithine derivatives, NG-acylated argininamides were obtained by guanidinylation with tailor-made mono-Boc-protected N-acyl-S-methylisothioureas. The compounds were investigated for Y2R antagonism (calcium assays), Y2R affinity, and NPY receptor subtype selectivity (flow cytometric binding assays). Most of the NG-substituted (S)-argininamides showed Y2R antagonistic activities and binding affinities similar to those of the parent compound, whereas NG-acylated or -carbamoylated analogues with a terminal amine were superior (Y2R: Ki and KB values in the low nanomolar range). This demonstrates that the basicity of the compounds, although 4-5 orders of magnitude lower than that of guanidines, is sufficient to form key interactions with acidic amino acids of the Y2R. The acylguanidines bind with high affinity and selectivity to Y2R over the Y1, Y4, and Y5 receptors. As derivatization of the amino group is tolerated, these compounds can be considered building blocks for the preparation of versatile fluorescent and radiolabeled pharmacological tools for invitro studies of the Y2R. The results support the concept of bioisosteric guanidine-acylguanidine exchange as a broadly applicable approach to retain pharmacological activity despite decreased basicity.
Guanidine-acylguanidine bioisosteric approach in the design of radioligands: Synthesis of a tritium-labeled NG-propionylargininamide ([3H]-UR-MK114) as a highly potent and selective neuropeptide Y Y1 receptor antagonist
Keller, Max,Pop, Nathalie,Hutzler, Christoph,Beck-Sickinger, Annette G.,Bernhardt, Günther,Buschauer, Armin
supporting information; experimental part, p. 8168 - 8172 (2009/12/07)
Synthesis and characterization of (R)-Nα-(2,2- diphenylacetyl)-N-(4-hydroxybenzyl)-Nω-([2,3- 3H]-propanoyl)-argininamide ([3H]-UR-MK114), an easily accessible tritium-labeled NPY Y1 receptor (Y1R) antagonist (KB: 0.8 nM, calcium assay, HEL cells) derived from the (R)-argininamide BIBP 3226, is reported. The radioligand binds with high affinity (KD, saturation: 1.2 nM, kinetic experiments: 1.1 nM, SK-N-MC cells) and selectivity for Y1R over Y2, Y 4, and Y5 receptors. The title compound is a useful pharmacological tool for the determination of Y1R ligand affinities, quantification of Y1R binding sites, and autoradiography.
Urethane protected derivatives of 1-guanylpyrazole for the mild and efficient preparation of guanidines
Bernatowicz, Michael S.,Wu, Youling,Matsueda, Gary R.
, p. 3389 - 3392 (2007/10/02)
Bis-urethane protected derivatives of 1-guanylpyrazole were prepared and found to readily react with relatively amines at room temperature to produce bis-protected guanidines in good yields. Simultaneous removal of both protecting groups from these products efficiently produced monosubstituted guanadines.