Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition

[Display omitted] This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and...

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Published in	Bioorganic & medicinal chemistry letters Vol. 26; no. 17; pp. 4282 - 4286
Main Authors	Wood, Michael R., Noetzel, Meredith J., Tarr, James C., Rodriguez, Alice L., Lamsal, Atin, Chang, Sichen, Foster, Jarrett J., Smith, Emery, Chase, Peter, Hodder, Peter S., Engers, Darren W., Niswender, Colleen M., Brandon, Nicholas J., Wood, Michael W., Duggan, Mark E., Conn, P. Jeffrey, Bridges, Thomas M., Lindsley, Craig W.
Format	Journal Article
Language	English
Published	England Elsevier Ltd 01.09.2016
Subjects	Allosteric Regulation Animals Central Nervous System - metabolism Drug Discovery Humans Ketones - chemical synthesis Ketones - chemistry Ketones - pharmacokinetics Molecular Structure Muscarinic acetylcholine receptor Positive allosteric modulator (PAM) Receptor, Muscarinic M1 - agonists Schizophrenia Structure-Activity Relationship Structure–Activity Relationship (SAR) Schizophrenia Positive allosteric modulator (PAM) M4 Structure–Activity Relationship (SAR) Muscarinic acetylcholine receptor M
Online Access	Get full text
ISSN	0960-894X 1464-3405 1464-3405
DOI	10.1016/j.bmcl.2016.07.042

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Abstract	[Display omitted] This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
AbstractList	This letter describes the chemical optimization of a novel series of M 4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo . SAR provided analogs for which M 4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M 4 PAM activity. [Display omitted] This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity. This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity. This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
Author	Lamsal, Atin Engers, Darren W. Chang, Sichen Hodder, Peter S. Wood, Michael W. Conn, P. Jeffrey Niswender, Colleen M. Rodriguez, Alice L. Tarr, James C. Noetzel, Meredith J. Smith, Emery Wood, Michael R. Bridges, Thomas M. Lindsley, Craig W. Brandon, Nicholas J. Chase, Peter Duggan, Mark E. Foster, Jarrett J.
AuthorAffiliation	e Amgen Inc., Thousand Oaks, CA, 91320 USA g Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA a Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA b Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA c Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA d The Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, 33458 USA f Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA
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CitedBy_id	crossref_primary_10_1016_j_bmcl_2019_06_032 crossref_primary_10_1016_j_bmcl_2017_04_043 crossref_primary_10_1016_j_neuropharm_2017_09_012 crossref_primary_10_3389_fphar_2020_606656 crossref_primary_10_1016_j_bmcl_2018_12_039 crossref_primary_10_1016_j_bmcl_2017_10_053 crossref_primary_10_1016_j_bmcl_2016_11_086 crossref_primary_10_1016_j_bmcl_2017_05_014 crossref_primary_10_1021_acschemneuro_7b00001 crossref_primary_10_1016_j_bmcl_2019_05_026
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Keywords	Schizophrenia Positive allosteric modulator (PAM) M4 Structure–Activity Relationship (SAR) Muscarinic acetylcholine receptor M
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Snippet	[Display omitted] This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN... This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional... This letter describes the chemical optimization of a novel series of M 4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional...
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SubjectTerms	Allosteric Regulation Animals Central Nervous System - metabolism Drug Discovery Humans Ketones - chemical synthesis Ketones - chemistry Ketones - pharmacokinetics Molecular Structure Muscarinic acetylcholine receptor Positive allosteric modulator (PAM) Receptor, Muscarinic M1 - agonists Schizophrenia Structure-Activity Relationship Structure–Activity Relationship (SAR)
Title	Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition
URI	https://dx.doi.org/10.1016/j.bmcl.2016.07.042 https://www.ncbi.nlm.nih.gov/pubmed/27476142 https://www.proquest.com/docview/1811843522 https://pubmed.ncbi.nlm.nih.gov/PMC4987221
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