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A New Lead Identification Strategy: Screening an sp 3 ‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives
Author(s) -
Karaki Fumika,
Umemoto Sho,
Ashizawa Karin,
Oki Tomoya,
Sato Noriko,
Ogino Takumi,
Ishibashi Naoto,
Someya Ryoto,
Miyano Kanako,
Hirayama Shigeto,
Uezono Yasuhito,
Fujii Hideaki
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900398
Subject(s) - lead compound , combinatorial chemistry , drug discovery , chemistry , lead (geology) , computational biology , steric effects , identification (biology) , stereochemistry , nanotechnology , biology , materials science , biochemistry , in vitro , botany , paleontology
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.