title: Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors.
abstract: The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States. Electronic address: dgoldberg@karospharma.com.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldberg
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Lombaert
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Aiello
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourassa
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Barucci
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Vishwas
authors.initials: V
authors.lastname: Paralkar
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: James
authors.initials: J
authors.lastname: Valentine
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: William
authors.initials: W
authors.lastname: Zavadoski
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D013141:Spiro Compounds; D012701:Serotonin; D011392:Proline; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase
keywords: 5-HT; Peripheral serotonin; Spirocycle; TPH1