title: Development of novel M1 antagonist scaffolds through the continued optimization of the MLPCN probe ML012.
abstract: This Paper describes the continued optimization of an MLPCN probe molecule M(1) antagonist (ML012) through an iterative parallel synthesis approach. After several rounds of modifications of the parent compound, we arrived at a new azetidine scaffold that displayed improved potency while maintaining a desirable level of selectivity over other muscarinic receptor subtypes. Data for representative molecules 7w (VU0452865) and 12a (VU0455691) are presented.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. bruce.j.melancon@vanderbilt.edu
authors: Bruce J
authors: BJ
authors: Melancon
authors: Thomas J
authors: TJ
authors: Utley
authors: Christian
authors: C
authors: Sevel
authors: Margrith E
authors: ME
authors: Mattmann
authors: Yiu-Yin
authors: YY
authors: Cheung
authors: Thomas M
authors: TM
authors: Bridges
authors: Ryan D
authors: RD
authors: Morrison
authors: Douglas J
authors: DJ
authors: Sheffler
authors: Colleen M
authors: CM
authors: Niswender
authors: J Scott
authors: JS
authors: Daniels
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Craig W
authors: CW
authors: Lindsley
authors: Michael R
authors: MR
authors: Wood
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D015335:Molecular Probes / Q000737:chemistry*; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D053961:Azabicyclo Compounds; D001384:Azetidines; D015335:Molecular Probes; C542801:N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide; D020033:Protein Isoforms; D043643:Receptor, Muscarinic M1; D013449:Sulfonamides; D013830:Thiadiazoles; C576464:VU0455691; C082735:azetidine; D003577:Cytochrome P-450 Enzyme System