title: Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors.
abstract: The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimamoto
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 606-0823, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Teruya
authors.affiliation: R&D Center, Protein Wave Co., Nara 631-0006, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sanjoh
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Yamashita
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: akaji@mb.kyoto-phu.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akaji
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000821:virology
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D011480:Protease Inhibitors; D053818:Chymases
keywords: Decahydroisoquinolin; Hydrophobic interaction; Inhibitor; SARS 3CL protease