Synthesis and Characterization of Bradykinin B₂ Receptor Agonists Containing Constrained Dipeptide Mimics

Abstract

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).

Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling

“…This slight reduction compared to pCinn ( 20 ) parallels that found in the more peptidic compounds, 6 vs 5 . Haic is a known dipeptide mimetic that has been used in protease inhibitor development,60,61 bradykinin antagonists,62 major histocompatibility complex antagonist studies,63 and opioid receptor agonists 64. This is the first reported use in an SH2 domain inhibitor.…”

Synthesis of optically active 1,5-benzothiazepines

“…o-Fluoronitrobenzene ( Solid-phase synthesis of optically active 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones, using cysteine derivatives as building blocks, has also been described in the literature. 29 Amblard et al [30][31][32][33] Its effectiveness stimulated the efforts to develop various synthetic protocols for its preparation. These efforts were further supported by the fact that nowadays only optically pure active ingredients are allowed to use for the production and sale of medicines.…”

Current Scenario of 1,4-Diazepines as Potent Biomolecules-A Mini Review

“…The first synthesis of spiro-1,4-diazepine-2,5-dione heterocycles (96) at the anomeric position of furano sugars were reported [126]. (98) and benzothiazepine [128] (Fig. 24).…”