Azepinone-Constrained Amino Acids in Peptide and Peptidomimetic Design

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

“…Azepinone scaffold has been utilized for the formation of constrained dipeptidic moieties such as Aba, 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba), and 4-mino-1,2,4,5-tetrahydro-indolo [2,3-c]azepin-3-one (Aia). Replacement of Tic-Gly in Dmt-Tic-Gly analogs with dipeptidic moieties, Aba-Gly and D Aia-Gly, shifted affinity and selectivity to afford a potent MOR agonist and DOR antagonist, respectively [ 283 , 284 , 285 , 286 ]. The same replacement effect was observed in DER tetrapeptide when Phe 3 -Gly 4 was substituted by Aba-Gly [ 287 ].…”

Solid-Phase Azopeptide Diels–Alder Chemistry for Aza-pipecolyl Residue Synthesis To Study Peptide Conformation

“…The therapeutic potential of peptides can be enhanced by synthetic modifications that preserve activity and improve bioavailability, stability, and selectivity . In light of the privileged role of β-turn secondary structures in molecular recognition, many methods have been particularly developed to synthesize rigid peptide turn surrogates . Effective approaches are however still needed for the introduction of specific turn geometry systematically into peptide structures using solid-phase chemistry to enable examination of their relevance for activity by library synthesis in biomedical research .…”

Peptidomimetic Synthesis by Way of Diastereoselective Iodoacetoxylation and Transannular Amidation of 7–9-Membered Lactams

“…In peptide mimicry, stereocontrolled ring synthesis is desired to replicate precisely the side chain and backbone orientations responsible for biological activity . Constrained dipeptide lactam and azabicyclo­[X.Y.0]­alkanone rings have shown great utility for the mimicry of biologically active peptide secondary structures. , Although the stereoselective synthesis and functionalization of small ring lactams have been effectively accomplished, their introduction into bicyclic motifs and the construction and modification of their larger 7–9-member ring counterparts remain two relatively unmet challenges . Employing unsaturated 7–9-membered lactams, stereocontrolled means have now been conceived for their conversion to fused bicycles composed of small ring systems (fused 5,5-, 5,6-, and 6,4-bicycles 1 – 5 ) as well as their functionalization (e.g., 6 – 8 , Figure ).…”

“…3,4 Although the stereoselective synthesis and functionalization of small ring lactams have been effectively accomplished, their introduction into bicyclic motifs and the construction and modification of their larger 7−9-member ring counterparts remain two relatively unmet challenges. 5 Employing unsaturated 7−9-membered lactams, stereocontrolled means have now been conceived for their conversion to fused bicycles composed of small ring systems (fused 5,5-, 5,6-, and 6,4-bicycles 1−5) as well as their functionalization (e.g., 6−8, Figure 1). Exploring the scope and limitations of this method, a set of turn mimics bearing ring substituents has been made for replicating peptide geometry.…”