Angiotensin II Analogues Encompassing 5,9- and 5,10-Fused Thiazabicycloalkane Tripeptide Mimetics

• Published in: Journal of medicinal chemistry Vol. 42; no. 22; pp. 4524 - 4537
• Main Authors: Johannesson, Petra, Lindeberg, Gunnar, Tong, Weimin, Gogoll, Adolf, Synnergren, Barbro, Nyberg, Fred, Karlén, Anders, Hallberg, Anders
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 04.11.1999
• Subjects: Angiotensin II - analogs & derivatives; Angiotensin II - chemical synthesis; Angiotensin II - chemistry; Angiotensin II - metabolism; Animals; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - metabolism; Binding, Competitive; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - metabolism; CHO Cells; Cricetinae; Medical sciences; Models, Molecular; Molecular Mimicry; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - metabolism; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Structure, Secondary; Radioligand Assay; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - metabolism; Stereoisomerism; Structure-Activity Relationship; Oligopeptides; Rat; Modeling; Octapeptide; Structure activity relation; Molecular model; Bicyclic compound; Peptidergic receptor; Angiotensin II; Chemical synthesis; Molecular rigidity; Sulfur nitrogen heterocycle; Peptidomimetic compound; Rodentia; Steric hindrance; In vitro; Vertebrata; Biological fixation; Mammalia; Cyclization; Sulfur peptide; Animal; Peptide synthesis; Solid phase; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991089q

A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt β-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3−5- and 5−7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT1 receptor affinity (K i = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT1 receptor.