title: Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.
abstract: Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: George O
authors.initials: GO
authors.lastname: Tora
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.affiliation: Chemical Development, Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Conlon
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Davis
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Umesh M
authors.initials: UM
authors.lastname: Hanumegowda
authors.affiliation: Department of Chemical Synthesis, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Hou
authors.affiliation: Chemical Development, Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hsiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Rudolph
authors.initials: R
authors.lastname: Krause
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Newton
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Raybon
authors.affiliation: Chemical Development, Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Rosner
authors.affiliation: Department of Chemical Synthesis, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Jung-Hui
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Taber
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: Department of Chemical Synthesis, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Wong
authors.affiliation: Department of Chemical Synthesis, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003866:Depressive Disorder / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005849:Gerbillinae; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D000071230:Transcriptional Regulator ERG / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D007191:Indazoles; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D000071230:Transcriptional Regulator ERG; C072312:ERG protein, human
keywords: Depression; asymmetric hydrogenation; hERG; ion channels; neurokinin 1; serotonin transporter inhibitor