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Metropolitan Government of Nashville-Davidson (balance), TN, United States

Bridges T.M.,Vanderbilt University | Bridges T.M.,Vanderbilt Specialized Chemistry Center | Kennedy J.P.,Vanderbilt University | Hopkins C.R.,Vanderbilt University | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties. © 2010 Elsevier Ltd. All rights reserved.


Bridges T.M.,Vanderbilt University | Bridges T.M.,Vanderbilt Specialized Chemistry Center | Phillip Kennedy J.,Vanderbilt University | Phillip Kennedy J.,Vanderbilt Specialized Chemistry Center | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) with the goal of developing a selective M1 PAM. An iterative library synthesis approach delivered a potent (M1 EC50 = 830 nM) and highly selective M1 PAM (>30 μM vs M2-M5). © 2010 Elsevier Ltd. All rights reserved.


Lamb J.P.,Vanderbilt University | Engers D.W.,Vanderbilt University | Engers D.W.,Vanderbilt Specialized Chemistry Center | Niswender C.M.,Vanderbilt University | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

This Letter describes a chemical lead optimization campaign directed at a weak mGlu5 NAM discovered while developing SAR for the mGlu 5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu5 NAMs, mGlu5 PAMs as well as mGlu5 partial antagonists. © 2010 Elsevier Ltd. All rights reserved.


Bridges T.M.,Vanderbilt University | Bridges T.M.,Vanderbilt Specialized Chemistry Center | Kennedy J.P.,Vanderbilt University | Kennedy J.P.,Vanderbilt Specialized Chemistry Center | And 12 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1-M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS. © 2009 Elsevier Ltd. All rights reserved.


Reid P.R.,Vanderbilt Institute of Chemical Biology Chemical Synthesis Core | Bridges T.M.,Vanderbilt University | Bridges T.M.,Vanderbilt Specialized Chemistry Center | Sheffler D.J.,Vanderbilt University | And 20 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio. © 2010 Elsevier Ltd. All rights reserved.

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