title: Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.
abstract: As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.
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: Cayman Chemical, 5025 Venture Dr., Ann Arbor, MI 48108, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Holt
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: D000818:Animals; D001665:Binding Sites; D004285:Dogs; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C000621039:KAR5417; D011355:Prodrugs; D011743:Pyrimidines; D013141:Spiro Compounds; D012701:Serotonin; C000621040:rodatristat; D011392:Proline; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase
keywords: 5-HT; Serotonin; TPH-1; Tryptophan hydroxylase-1