155172-73-9Relevant articles and documents
2,5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics
Borthwick, Alan D.,Davies, Dave E.,Exall, Anne M.,Livermore, David G.,Sollis, Steve L.,Nerozzi, Fabrizio,Allen, Michael J.,Perren, Marion,Shabbir, Shalia S.,Woollard, Patrick M.,Wyatt, Paul G.
, p. 6956 - 6969 (2007/10/03)
A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pKi > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2′,4′-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pKi = 8.9) that has > 1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR10 = 0.44 mg/kg iv).
Design and Synthesis of Side-Chain Conformationally Restricted Phenylalanines and Their Use for Structure-Activity Studies on Tachykinin NK-1 Receptor
Josien, Hubert,Lavielle, Solange,Brunissen, Alie,Saffroy, Monique,Torrens, Yvette,et al.
, p. 1586 - 1601 (2007/10/02)
Constrained analogues of phenylalanine have been conceptually designed for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), two aromatic residues important for the pharmacological properties of SP, i.e., L-tetrahydroisoquinoleic acid, L-diphenylalanine, L-9-fluorenylglycine (Flg), 2-indanylglycine, the diastreomers of L-1-indanylglycine (Ing) and L-1-benzindanylglycine (Bfi), and the Z and E isomers of dehydrophenylalanine (ΔZPhe, ΔEPhe).Binding studies were performed with appropriate ligands and tissue preparations allowing the discrimination of the three tachykinin binding sites, NK-1, NK-2, and NK-3.The potencies of these agonists were evaluated in the guinea pig ileum bioassay.According to the binding data, we can conclude that the S7 subsite is small, only the gauche(-) probe 7>SP presents a high affinity for specific NK-1 binding sites.Surprisingly, the EPhe7>SP analogue, which projects the aromatic ring toward the trans orientation, is over 40-fold more potent than the Z isomer, ZPhe7>SP.A plausible explanation of these conflictual results is that either the binding protein quenches the minor trans rotamer of 7>SP in solution or this constrained amino acid side chain rotates when inserted in the protein.In position 8, the high binding affinities of 8>SP and 8>SP suggest that the S8 subsite is large enough to accept two aromatic rings in the gauche(-) and one aromatic ring in the trans direction.Peptides bearing two conformational probes in positions 7, 8 or 9 led to postulate that S7, S8, and S9 subsites are independent from each other.The volumes available for side chains 7 and 8 can be estimated to be close to 110 and 240 Angstroem3, respectively.The large volume of the S8 subsite raises question on the localization of the SP-binding site in the NK-1 receptor.If SP were to bind in the transmembrane domains, the cleft defined by the seven transmembrane segments must rearrange during the binding process in order to bind a peptide in an α-helical structure and at least one large binding subsite in position 8.Thus, indirect topographical analysis with constrained amino acids might contribute to the analysis of the receptor/ligand dynamics.Finally, this study demonstrates that a good knowledge of the peptidic backbone structure and a combination of constrained amino acids are prerequisites to confidently attribute the preferred orientation(s) of an amino acid side chain.
