title: Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists.
abstract: A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro-3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), α(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayako.moritomo@astellas.com.
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Takaho
authors.initials: T
authors.lastname: Matsuzawa-Nomura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Development, Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
authors.forename: Hirotsune
authors.initials: H
authors.lastname: Itahana
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Oku
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Akuzawa
authors.affiliation: Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor
keywords: 5-HT(2B) receptor; 5-HT(7) receptor; Dual antagonist; Migraine; Optical resolution