Journal article
Challenges in the development of an M 4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs
Bioorganic & medicinal chemistry letters, Vol.27(2), pp.171-175
01/15/2017
DOI: 10.1016/j.bmcl.2016.11.086
PMCID: PMC5340297
PMID: 27939174
Abstract
This letter describes the chemical optimization of a novel series of M
positive 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).
Details
- Title: Subtitle
- Challenges in the development of an M 4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs
- Creators
- Michael R Wood - Vanderbilt UniversityMeredith J Noetzel - Vanderbilt UniversityMichael S Poslusney - Vanderbilt University Medical CenterBruce J Melancon - Vanderbilt UniversityJames C Tarr - Vanderbilt University Medical CenterAtin Lamsal - Vanderbilt University Medical CenterSichen Chang - Vanderbilt University Medical CenterVincent B Luscombe - Vanderbilt UniversityRebecca L Weiner - Vanderbilt UniversityHyekyung P Cho - Vanderbilt UniversityMichael Bubser - Vanderbilt University Medical CenterCarrie K Jones - Vanderbilt University Medical CenterColleen M Niswender - Vanderbilt UniversityMichael W Wood - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.Darren W Engers - Vanderbilt UniversityNicholas J Brandon - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.Mark E Duggan - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.P Jeffrey Conn - Vanderbilt UniversityThomas M Bridges - Vanderbilt UniversityCraig W Lindsley - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry letters, Vol.27(2), pp.171-175
- DOI
- 10.1016/j.bmcl.2016.11.086
- PMID
- 27939174
- PMCID
- PMC5340297
- NLM abbreviation
- Bioorg Med Chem Lett
- ISSN
- 0960-894X
- eISSN
- 1464-3405
- Grant note
- U54 MH084659 / NIMH NIH HHS U01 MH087965 / NIMH NIH HHS R01 MH073676 / NIMH NIH HHS R37 NS031373 / NINDS NIH HHS
- Language
- English
- Date published
- 01/15/2017
- Academic Unit
- Pulmonary Medicine; Stead Family Department of Pediatrics
- Record Identifier
- 9984353937002771
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