title: Synthesis, structure-activity relationships and biological evaluation of 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 negative allosteric modulators.
abstract: The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: wataru-hirose@ds-pharma.co.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Hirose
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Momoe
authors.initials: M
authors.lastname: Kassai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takata
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Imai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: yoshida-k@phs.osaka-u.ac.jp.
authors.forename: Kohzo
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000621454:4,5,6,7-tetrahydropyrazolopyrazine; D000928:Antidepressive Agents; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: CNS drug discovery; Hit to lead studies; Negative allosteric modulator; mGluR5