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

O'Reilly M.C.,Vanderbilt University | Scott S.A.,Vanderbilt University | Brown H.A.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Specialized Chemistry Center for Probe Development
Bioorganic and Medicinal Chemistry Letters | Year: 2014

This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors. © 2014 Elsevier Ltd. All rights reserved. Source


Wen W.,Northwest University, China | Wen W.,Vanderbilt University | Wu W.,Northwest University, China | Weaver C.D.,Vanderbilt University | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

This Letter describes the on-going SAR efforts based on ML297, a potent, efficacious and selective GIRK1/2 activator (∼10-fold vs GIRK1/4 and inactive on GIRK2/3) via an iterative parallel synthesis approach. The chemical optimization at the 3-position of pyrazole within ML297 indicated that various functionalized 3-cyclopropyl moieties modulated GIRK pharmacology between inhibitor/activator within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas. Importantly, novel 'molecular switches' that modulated the mode of pharmacology from inhibitor to activator was discovered on both the 3-cyclopropyl and N-phenyl moiety of the pyrazole core, providing the first highly selective GIRK1/2 activator. © 2014 Elsevier Ltd. All rights reserved. Source


Wen W.,Northwest Agriculture and Forestry University | Wen W.,Vanderbilt University | Wu W.,Northwest Agriculture and Forestry University | Romaine I.M.,Vanderbilt University | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (∼10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity. © 2013 Elsevier Ltd. All rights reserved. Source


Ramos-Hunter S.J.,Vanderbilt University | Engers D.W.,Vanderbilt University | Engers D.W.,Vanderbilt Specialized Chemistry Center for Probe Development | Kaufmann K.,Vanderbilt University | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow. © 2013 Elsevier Ltd. All rights reserved. Source


Engers D.W.,Vanderbilt University | Engers D.W.,Vanderbilt Specialized Chemistry Center for Probe Development | Frist A.Y.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation. © 2013 Elsevier Ltd. All rights reserved. Source

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