Macrocycles as Templates for Diversity Generation in Drug Discovery

Ring‐Expansion Approach to Medium‐Sized Lactams and Analysis of Their Medicinal Lead‐Like Properties

“…[1] However,i nr ecent years, there has been as ignificant rise in interest in the medicinal applicationso fl arger ring compounds; [2] various methods to generate libraries of such compounds for bioassay have been developed, with medium-sized (eight-eleven-membered rings) and macrocyclic scaffolds (12 +)b oth having been examined. [3,4] Larger ring scaffolds generally have sufficiently welldefined conformations to bind to target receptors without major entropic penalties, [5] but are more flexible than their smaller ring analogues and hencea ble to changet heir conformation to facilitate binding if needed. They have also been shown to exhibit improvedb ioavailability,e nhanced cell permeability and greater metabolic stability compared to related linear analogues in various studies.…”

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds

“…1). 1,2,[6][7][8][9][10][11][12] However, despite such potentially valuable properties, macrocyclic peptidomimetics are considered to be a relatively poorly explored structural class within drug discovery. 1,2,9,13 This can be attributed to a lack of general methods for producing macrocyclic peptidomimetics collections with broad structural (chemical) diversity and thus functional diversity (that is, displaying a broad range of biological activities).…”