title: Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors.
abstract: An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States. Electronic address: dgoldberg@kineta.us.
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: Cayman Chemical, 5025 Venture Dr., Ann Arbor, MI 48108, United States.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Stein
authors.affiliation: Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
authors.forename: Jim
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: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase; D019791:Guanidine
keywords: 5-HT; Acyl guanidine; Medicinal chemistry; Peripheral serotonin; TPH1