Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 2

Abstract

Applications of piperazine and homopiperazine in drug design are well-established, and these heterocycles have found use as both scaffolding and terminal elements and also as a means of introducing a water-solubilizing element into a molecule. In the accompanying review (10.1021/acs.jafc.2c00726), we summarized applications of piperazine and homopiperazine and their fused ring homologues in bioactive compound design along with illustrations of the use of 4-substituted piperidines and a sulfoximine-based mimetic. In this review, we discuss applications of pyrrolidine- and fused-pyrrolidine-based mimetics of piperazine and homopiperazine and illustrate derivatives of azetidine that include stretched and spirocyclic motifs, along with applications of a series of diaminocycloalkanes.

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1

“…In addition, we have highlighted examples of the potential for 4-fluoro-, 4-hydroxy-, and 4-cyanopiperidines and the interesting cyclic sulfoximine 1λ 6 -thiomorpholine-1-imine 1-oxide to function as mimics of piperazine. In the accompanying article (10.1021/acs.jafc.2c00729), we extend the discussion and exemplification of piperazine and homopiperazine bioisosteres by exploring the design and applications of pyrrolidines with fused heterocyclic and carbocyclic rings, azetidines, spiro heterobicyclic ring systems, cubanes, and bicyclopentane derivatives in the design of biologically active compounds …”

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…Recent reviews have highlighted that piperazines and particularly homopiperazines (i.e., suvorexant ) act as almost universal building blocks around which several unique ligands, targeting numerous families of GPCRs, have been designed 93,94 . Indeed, the above described octahydropyrrolo[3,4‐c]pyrroles, used as ring linker in seltorexant , and corresponding analogs, has been described as a bioisoster for homopiperazine, supported by the similar pharmacological profiles of orexin ligands presenting either one of them.…”

“…93,94 Indeed, the above described octahydropyrrolo [3,4-c]pyrroles, used as ring linker in seltorexant, and corresponding analogs, has been described as a bioisoster for homopiperazine, supported by the similar pharmacological profiles of orexin ligands presenting either one of them. This bioisosteric approach has been expanding the drug design of the chemical space around diamine-linkers, and in 2022, Meanwell et al 93,94 proposed that pyrrolidine-diamine rings could replace homopiperazines and octahydropyrrolo [3,4-c]pyrroles as scaffolds to potentially target several classes of receptors, including the OX-R subtypes. The most fascinating aspect of using any of the linkers depicted in Figure 22 is the almost unlimited range of opportunities for developing unexplored F I G U R E 23 Drug design campaigns before 2017 conducted by (A) Merck to identify potent OX-R antagonists, based on proline bis-amides, and homopiperazine rings, leading to the characterization of suvorexant; (B) Novartis to identify potent 2-SORAs using spirocyclic amino-amides as replacements for homopiperazine rings; (C) Takeda to synthesize potent 2-SORAs using spiropiperidine nuclei.…”

New Advances in the Synthesis of Emerging Cyclic Amidrazones to Foster Bioisosterism of Azaheterocycles

“…The unique intrinsic properties of nitrogen have a key impact on steric and electrostatic interactions, as well as on the conformation of a small molecule. [5] The attention of our research group was drawn by the poorly explored 1,4,5,6-tetrahydro-1,2,4-triazine also called cyclic amidrazone. These entities can be regarded as bioisoster of a large range of aza-heterocyclic ring systems (Figure 1).…”