Double-bonded azacycles used as bioisosteric moieties in drug discovery

This article presents the synthetic methods of double-bonded azacycles and their applications as bioisosteres in drug discovery. Our focus was on the creation of fragment (2) (1,1′,4,4′-tetrahydro-2H,2′H-3,3′-biazetylidene) and its utilization as a bioisostere in compound (34). The analysis of how FT-4202 (etavopivat), a new activator of the pyruvate kinase, and compound (34) bind with the PKR protein showed comparable interactions with the adjacent amino acids. Through biochemical and cellular evaluations, it was also demonstrated that the activities of compound (34) and its analogs align well with FT-4202. This finding points to the promising prospect of utilizing fragment (2) as a bioisostere for fragment (1).