199110-64-0Relevant articles and documents
Synthesis of Fmoc-Protected Arylphenylalanines (Bip Derivatives) via Nonaqueous Suzuki-Miyaura Cross-Coupling Reactions
Qiao, Jennifer X.,Fraunhoffer, Kenneth J.,Hsiao, Yi,Li, Yi-Xin,Wang, Chunlei,Wang, Tammy C.,Poss, Michael A.
, p. 9499 - 9506 (2016)
A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.
Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile
Tran, Kien,Van Den Hauwe, Robin,Sainsily, Xavier,Couvineau, Pierre,C?té, Jér?me,Simard, Louise,Echevarria, Marco,Murza, Alexandre,Serre, Alexandra,Théroux, Léa,Saibi, Sabrina,Haroune, Lounès,Longpré, Jean-Michel,Lesur, Olivier,Auger-Messier, Mannix,Spino, Claude,Bouvier, Michel,Sarret, Philippe,Ballet, Steven,Marsault, éric
, p. 5345 - 5364 (2021/02/16)
Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.
Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template
Gall, Flavio M.,Hohl, Deborah,Frasson, David,Wermelinger, Tobias,Mittl, Peer R. E.,Sievers, Martin,Riedl, Rainer
, p. 4051 - 4055 (2019/02/16)
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nm) and MMP-9 (IC50: 140 nm).
Ligands for opioid receptors
-
, (2008/06/13)
The present invention provides compounds, and pharmaceutical preparations thereof, that bind selectively to mammalian opioid receptors. The present set of compounds comprises full agonists, partial agonists, and antagonists of mammalian opioid receptors.
