title: Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists.
abstract: We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives 8. As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than 3. Some of these compounds also showed comparable aqueous solubility to 3.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Gamo
authors.affiliation: Department of Biotechnology, Faculty of Life and Environmental Sciences, University of Yamanashi, 4-3-37 Takeda, Kofu City, Yamanashi 400-8510, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ohashi
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Waki
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.affiliation: Department of Life Science, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan.
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshimaku, Tokyo 171-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tokiwa
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: miyachi@pharm.okayama-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047495:PPAR gamma
keywords: Cyclic amine; Molecular dynamics simulation; Peroxisome proliferator-activated receptor gamma