title: Challenges in the development of an M4PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.
abstract: This letter describes the chemical optimization of a novel series of M4positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Poslusney
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Atin
authors.initials: A
authors.lastname: Lamsal
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sichen
authors.initials: S
authors.lastname: Chang
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Luscombe
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Weiner
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: thomas.m.bridges@vanderbilt.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000599366:5-amino-3,4-dimethyl-N-(4-((trifluoromethyl)sulfonyl)benzyl)thieno(2,3-c)pyridazine-6-carboxamide; D008024:Ligands; D033703:Nucleoside Transport Proteins; D011724:Pyridazines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; C444719:adenosine transporter
keywords: M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-activity relationship (SAR)