Rationally designed non-peptides: Variously substituted piperazine libraries for the discovery of bradykinin antagonists and other G-protein-coupled receptor ligands (original) (raw)
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Structure-based design of six novel classes of nonpeptide antagonists of the bradykinin B2 receptor
Bioorganic & Medicinal Chemistry Letters, 2000
ÐSix classes of nonpeptide bradykinin antagonists were designed using a template derived from structural studies of peptide antagonists. Several compounds from each class were synthesized and assayed for binding to the human bradykinin B 2 receptor. Each family showed compounds active at the level of the smallest template peptide; three classes contained compounds with K d <8 mM. These results provide diverse leads for a medicinal chemistry-based optimization program.
Design and Synthesis of New Linear and Cyclic Bradykinin Antagonists
Journal of Medicinal Chemistry, 1996
We report here on the synthesis and pharmacological properties of a new series of small linear and cyclic peptides derived from the five C-terminal amino acid residues of second-generation bradykinin receptor antagonists. Variations of the two first residues of the pentapeptide (Thi-Ser-D-Tic-Oic-Arg) were shown to modulate the biological activities of the analogs on bradykinininduced smooth muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific of the B2 bradykinin receptor. Several analogs showed pA 2 values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg-], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA 2 of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 receptor. The pK B values obtained for these compounds on these tissue preparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA 2 < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II′-turn structure. This analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.
Novel non-peptide lead structures for bradykinin B2-receptor antagonists
Letters in Peptide Science, 2000
A series of new non-peptide Bradykinin (BK) B2-receptor antagonists is reported. These new leads belong to a larger set including both commercially or otherwise available potential candidates found by proprietary database searches using 3D-pharmacophore models as query, and several bis-benzamidino compounds selected from our tryptase-like protease inhibitor library on the basis of topological considerations, derived from the same models. Some of these compounds show functional competitive antagonistic activity, inhibiting in vitro the BK-induced contraction of isolated guinea-pig ileum (GPI) and rat uterus with a pA2 up to 5.3 and 7.0, respectively. They display also binding affinity (ICs0 up to 0.56 #M) to the BK Bz-receptor in radioligand binding assays on GPI membrane preparations and on human IMR-90 fetal lung fibroblast cells expressing this receptor subtype. Furthermore, the results with the commercially available compounds, in some cases developed as therapeutics, show that the used 3D-pharmacophore model allows to predict to some certainty possible side actions of potential drugs.
International Journal of Food Microbiology, 2011
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC 50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Journal of Medicinal Chemistry, 1999
We have previously shown that substitution of the D-Tic-Oic dipeptide by a (3S)-[amino]-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (D-BT) moiety in the bradykinin B 2 receptor antagonist HOE 140 resulted in a full potent and selective bradykinin B 2 receptor agonist (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-Arg-OH, JMV1116) exhibiting a high affinity for the human receptor (K i 0.7 nM). In the present study, we have investigated the effects of replacement of the D-Tic-Oic moiety by various constrained dipeptide mimetics. The resulting compounds were tested for their binding affinity toward the cloned human B 2 receptor and for their functional interaction with the bradykinin-induced contraction of isolated human umbilical vein. Subsequently, we have designed novel bradykinin B 2 receptor agonists which are likely to be resistant to enzymatic cleavage by endopeptidases and which might represent interesting new pharmacological tools. In an attempt to increase the potency of compound JMV1116, both its N-terminal part and the D-BT moiety were modified. Substitution of the D-arginine residue by a L-lysine residue led to a 10-fold more potent bradykinin B 2 ligand [compound 22 (JMV1465) (K i 0.07 nM)], retaining full agonist activity on human umbilical vein. Substitution of the D-BT moiety by a (3S)-[amino]-5-(carbonylmethyl)-2,3-dihydro-8-methyl-1,5-benzothiazepin-4(5H)one [D-BT(Me)] moiety led to compound 23 (JMV1609) which exhibited a higher agonist activity (pD 2 ) 7.4) than JMV1116 (pD 2 ) 6.8).
Bioorganic & Medicinal Chemistry Letters, 2013
A novel approach to the synthesis of substituted piperazines and their investigation as N-type calcium channel blockers is presented. A common scaffold exhibiting high activity as N-type blockers is N-substituted piperazine. Using recently developed titanium and zirconium catalysts, we describe the efficient and modular synthesis of 2,5-asymmetrically disubstituted piperazines from simple amines and alkynes. The method requires only three isolation/purification protocols and no protection/deprotection steps for the diastereoselective synthesis of 2,5-dialkylated piperazines in moderate to high yield. Screening of the synthesized piperazines for N-type channel blocking activity and selectivity shows the highest activity for a compound with a benzhydryl group on the nitrogen (position 1) and an unprotected alcohol-functionalized side chain.
A series of sixteen novel substituted piperidines and (2-methoxy-phenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-[(piperidin-4-yl)methyl]piperazine. Biological evaluation of the synthesized compounds was illustrated by seven compounds, of which 1-(2-methoxy-phenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine had the highest affinity for the dopamine D 2 receptor. For all seven selected compounds, docking analysis was performed in order to establish their structure-to-activity relationship.
Bioorganic & Medicinal Chemistry Letters, 2008
Replacement of the core b-amino acid in our previously reported piperidine acetic acid and b-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC 50 s < 0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.