Design and synthesis of conformationally restricted renin inhibitors

Progress in the Discovery of BACE Inhibitors

“…Macrocyclic inhibitors of renin [107] and HIV1 protease [108][109][110][111] have been prepared in a similar fashion. BACE inhibitors using this structural motif include a series of ether-linked macrocycles based on the HEA isostere containing a dipeptide 60 [112] and similar structures containing dicarboxamides 61 [113] from the Pharmacia/Elan team.…”

Direct Renin Inhibitors as a New Therapy for Hypertension

“…Design efforts therefore were aimed at maximizing the hydrophobic interactions to this key binding site by covalently linking the P 3 and P 1 side chains and ultimately at identifying novel structural classes of small-molecule DRIs with enhanced oral efficacy. 13,[46][47][48] Conformational constraints have been introduced in peptide-based peptidomimetics by cross-linking alternate side chains to enhance potency and selectivity by locking the inhibitor in the bound conformation and in addition to potentially improve the PK properties of the more flexible acyclic congeners. 13,23a,23b,46 The macrocyclic inhibitor 15 bearing a ψ[CH 2 NH]-reduced amide isostere (Figure 7) was 5 times more potent in vitro compared to the acyclic P 1 cyclohexylalanine-based analogue.…”

“…13,23a,23b,46 The macrocyclic inhibitor 15 bearing a ψ[CH 2 NH]-reduced amide isostere (Figure 7) was 5 times more potent in vitro compared to the acyclic P 1 cyclohexylalanine-based analogue. 46 While macrocyclization between the P 3 and P 1 side chains of peptidomimetic DRIs has found only limited application, in contrast to substantial efforts made for the design of P 3 -P 1 -linked BACE-1 macrocyclic inhibitors, 40 the spatial proximity of other recognition sites has attracted more interest and provided potent macrocyclic TSA inhibitors of renin. 23a,b Dihydroxyethylene isostere peptidomimetics with topographically modified P 1 (fP 3 ) side chains (16, Figure 7) have been explored by extending the P 1 cyclohexyl directly toward the S 3 binding pocket and by removing the linkage of P 3 to the peptide backbone.…”

“…The formation of large-surface van der Waals contacts to the hydrophobic amino acids lining the S 3 −S 1 cavity was considered to be energetically favorable as a driving force for binding affinity. Design efforts therefore were aimed at maximizing the hydrophobic interactions to this key binding site by covalently linking the P 3 and P 1 side chains and ultimately at identifying novel structural classes of small-molecule DRIs with enhanced oral efficacy. ,− Conformational constraints have been introduced in peptide-based peptidomimetics by cross-linking alternate side chains to enhance potency and selectivity by locking the inhibitor in the bound conformation and in addition to potentially improve the PK properties of the more flexible acyclic congeners. ,,, The macrocyclic inhibitor 15 bearing a ψ[CH 2 NH]-reduced amide isostere (Figure ) was 5 times more potent in vitro compared to the acyclic P 1 cyclohexylalanine-based analogue . While macrocyclization between the P 3 and P 1 side chains of peptidomimetic DRIs has found only limited application, in contrast to substantial efforts made for the design of P 3 −P 1 -linked BACE-1 macrocyclic inhibitors, the spatial proximity of other recognition sites has attracted more interest and provided potent macrocyclic TSA inhibitors of renin. , …”

Irritants: a modern redefining of relevance to the armed forces and the prospect of creating medical means of protection

“…Синтетические антагонисты TRPA1 (описание в тексте) [32]. На рисунке 1 также представлены трициклический антагонист TRPA1 (формула 8), эффективный в наномолярных концентрациях, однако имеющий потенциально токсичный фрагмент тиомочевины, что ограничило его клинические исследования [17]; гетероциклический амид (формула 9), который обладает обезболивающим эффектом при воздействии на мышей горчичным маслом; соединение (формула 10), карбаматный фрагмент которого придаёт электрофильные свойства, что свидетельствует о ковалентном связывании антагониста с TRPA1 [9]; вещества АР-18 [14] и A967079 [20] (формулы 11 и 12), которые, являясь производными оксимов, ингибируют TRPA1 в микромолярных концентрациях; производное декалина AZ465 (формула 13) [26].…”