title: Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility.
abstract: In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.
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: Department of Biotechnology, Faculty of Life and Environmental Sciences, University of Yamanashi, 4-4-37 Takeda, Kofu City, Yamanashi 400-8510, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of Cell Biology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Endy Widya
authors.initials: EW
authors.lastname: Putranto
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Waku
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: Hiromi
authors.initials: H
authors.lastname: Nobusada
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: Ken
authors.initials: K
authors.lastname: Kataoka
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 Surgical Oncology, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Institute for Protein Research, Osaka University, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: Department of Cell Biology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
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: D041721:3T3-L1 Cells; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001593:Benzyl Compounds; D047495:PPAR gamma; D010666:Phenylpropionates