Primary Pharmacology Group
Primary Pharmacology Group
Pettersson M.,Neuroscience and Pain Medicinal Chemistry |
Johnson D.S.,Neuroscience and Pain Medicinal Chemistry |
Rankic D.A.,Neuroscience and Pain Medicinal Chemistry |
Kauffman G.W.,Neuroscience and Pain Medicinal Chemistry |
And 19 more authors.
MedChemComm | Year: 2017
Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds. © 2017 The Royal Society of Chemistry.
Kung D.W.,Worldwide Medicinal Chemistry |
Griffith D.A.,Worldwide Medicinal Chemistry |
Esler W.P.,Metabolic and Endocrine Diseases Research Unit |
Vajdos F.F.,Structural Biology |
And 19 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015
A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM. © 2015 Elsevier Ltd. All rights reserved.
Bhattacharya S.K.,Worldwide Medicinal Chemistry |
Andrews K.,Cardiovascular and Metabolic Research Unit |
Beveridge R.,Worldwide Medicinal Chemistry |
Cameron K.O.,Worldwide Medicinal Chemistry |
And 24 more authors.
ACS Medicinal Chemistry Letters | Year: 2014
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials. © 2014 American Chemical Society.
PubMed | Pfizer, Structural Biology, Primary Pharmacology Group, Metabolic and Endocrine Diseases Research Unit and 2 more.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015
A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 M.
Smith D.L.,Pfizer |
Davoren J.E.,Pfizer |
Edgerton J.R.,Pfizer |
Lazzaro J.T.,Primary Pharmacology Group |
And 4 more authors.
Molecular Pharmacology | Year: 2016
Selective activation of the M1 muscarinic acetylcholine receptor (mAChR) via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. Herein, we describe the characterization of an M1 PAM radioligand, 8-((1S,2S)-2-hydroxycyclohexyl)-5-((6-(methyl- T3)pyridin-3-yl)- methyl)-8,9-dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one ([3H]PT-1284), as a tool for characterizing the M1 allosteric binding site, as well as profiling novel M1 PAMs. 8-((1S,2S)-2- Hydroxycyclohexyl)-5-((6-methylpyridin-3-yl)methyl)-8,9- dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one (PT-1284 (1)) was shown to potentiate acetylcholine (ACh) in an M1 fluorometric imaging plate reader (FLIPR) functional assay (EC50, 36 nM) and carbachol in a hippocampal slice electrophysiology assay (EC50, 165 nM). PT-1284 (1) also reduced the concentration of ACh required to inhibit [3H]N-methylscopolamine ([3H]NMS) binding to M1, left-shifting the ACh Ki approximately 19-fold at 10 mM. Saturation analysis of a human M1 mAChR stable cell line showed that [3H]PT-1284 bound to M1 mAChR in the presence of 1 mMAChwith Kd, 4.23 nM, and saturable binding capacity (Bmax), 6.38 pmol/mg protein. M1 selective PAMs were shown to inhibit [3H]PT-1284 binding in a concentration-responsivemanner,whereas M1 allosteric and orthosteric agonists showed weak affinity (.30mM). A strong positive correlation (R2 5 0.86) was found to exist between affinity values generated for nineteen M1 PAMs in the [3H]PT-1284 binding assay and the EC50 values of these ligands in a FLIPR functional potentiation assay. These data indicate that there is a strong positive correlation between M1 PAM binding affinity and functional activity, and that [3H]PT-1284 can serve as a tool for pharmacological investigation of M1 mAChR PAMs. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.