Multicomponent Macrocyclic IL-17a Modifier

Abstract

IL-17a is a major inflammation target, with several approved antibodies in clinical use. Small-molecule IL-17a antagonists are an emerging hot topic, with the recent advancement of three compounds into clinical trials. Here, we describe the design, discovery, synthesis, and screening of macrocyclic compounds that bind to IL-17a. We found that all currently described IL-17a modifiers belong to the same pharmacophore model, likely resulting in a similar receptor binding mode on IL-17a. A pipeline of pharmacophore analysis, virtual screening, resynthesis, and protein biophysics resulted in a potent IL-17a macrocyclic modifier.

Instant Macrocyclizations via Multicomponent Reactions

“…7,8 The dynamic changes in their conformation combined with their high surface area in certain protein−protein interactions, which takes advantage of entropic factors, make macrocycles an attractive solution to many targets previously undruggable with typical small molecules (MW ≤ 500 Da). 2,3,7,9 Consequently, since 2014, more than 19 macrocycles have been approved by FDA for the treatment of various diseases and conditions: cancer, 10,11 hepatorenal syndrome, 12 obesity, 13 bacterial and viral infections, 14,15 radiopharmaceuticals, 16 immuno-inflammatory diseases, 17 and sexual disorders 18 (Figure 1). Moreover, they have been employed as spike/ACE2 inhibitors for COVID-19.…”

“…Arguably, macrocycles belong to one of the hottest “new” modalities of the last five years. − Although initially there was much skepticism surrounding the use of macrocycles in drug discovery, mostly because of the increased molecular weight and polarity, they were soon found to be highly promising emerging entities. , The dynamic changes in their conformation combined with their high surface area in certain protein–protein interactions, which takes advantage of entropic factors, make macrocycles an attractive solution to many targets previously undruggable with typical small molecules (MW ≤ 500 Da). ,,, Consequently, since 2014, more than 19 macrocycles have been approved by FDA for the treatment of various diseases and conditions: cancer, , hepatorenal syndrome, obesity, bacterial and viral infections, , radiopharmaceuticals, immuno-inflammatory diseases, and sexual disorders (Figure ). Moreover, they have been employed as spike/ACE2 inhibitors for COVID-19 .…”

Ugi 5-center-4-component reaction of α-Amino Aldehydes/Deprotection/Cyclization sequence leading to substituted 2-oxopiperazine derivatives

“…Among the known MCRs, the isocyanide-based Ugi reaction [2] has received much attention in medicinal [3,4] and macrocyclic chemistry [5,6,7] chemical biology and bioconjugation [8, 9,10] as well as in natural product synthesis [11,12]. Several variants of this condensation have been developed, the Ugi three-(U-3CR) [13,14] and four-component reactions (U-4CR) [15] being most extensively studied (Scheme 1).…”

Ugi 5-center-4-component reaction of α-amino aldehydes and its application in synthesis of 2-oxopiperazines

“…Among the known MCRs, the isocyanide-based Ugi reaction [ 2 ] has received much attention in medicinal [ 3 , 4 ] and macrocyclic chemistry [ 5 – 7 ], chemical biology and bioconjugation [ 8 – 10 ], as well as in natural product synthesis [ 11 , 12 ]. Several variants of this condensation have been developed, the Ugi three- (U-3CR) [ 13 , 14 ] and four-component reactions (U-4CR) [ 15 ] being most extensively studied (Scheme 1 ).…”