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.