A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives. (20th September 2019)

• Record Type: Journal Article
• Authors: Karaki, Fumika; Umemoto, Sho; Ashizawa, Karin; Oki, Tomoya; Sato, Noriko; Ogino, Takumi; Ishibashi, Naoto; Someya, Ryoto; Miyano, Kanako; Hirayama, Shigeto; Uezono, Yasuhito; Fujii, Hideaki
• Is Part Of: ChemMedChem. Volume 14:Number 21(2019)
• Page Start: 1840
• Page End: 1848
• Publication Date: 2019-09-20
• Subjects: 7-azanorbornane -- drug design -- lead identification -- medicinal chemistry -- sp3 carbon atoms; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900398
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Although the advantages of sp 3 ‐rich, sterically complicated molecules in drug development have been pointed out, modern screening libraries are filled with planar, sp 2 ‐rich components. Compounds that are sp 3 ‐rich are difficult to synthesize, and thus we aimed to invent an efficient method to construct sp 3 ‐rich libraries. By modifying sp 3 ‐rich 7‐azanorbornane scaffolds through click chemistry, we efficiently prepared a small set of compounds. These compounds were not only sp 3 ‐rich, but also had sufficient "lead‐like" properties in view of molecular weights and hydrophobicity. Screening assays of this library provided weak κ opioid receptor agonists and growth hormone secretagogue receptor agonists with high hit rates. These results indicate that the 7‐azanorbornane scaffold may be a "privileged structure" for lead identification in drug discovery. Abstract : Privileged structure for hits : Despite the significance of sp 3 ‐hybridized carbons in today's medicinal chemistry, modern screening libraries are lacking in sp 3 ‐rich components. Herein we propose a novel and efficient strategy to construct an sp 3 ‐rich library with "lead‐like" properties. By modifying the sp 3 ‐rich 7‐azanorbornane scaffold through click chemistry, we prepared a small‐sized library. Screening for some receptors furnished several bioactive agents with high hit rates.