Publications by authors named "Virginia Berry"

8 Publications

  • Page 1 of 1

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel Na1.7.

J Pharmacol Exp Ther 2017 07 4;362(1):146-160. Epub 2017 May 4.

Department of Neuroscience (T.J.K., R.Y., S.A, C.P.I., M.J., D.J., J.H.L., S.G.L., J.Li., D.L., J.Lu., D.M., D.O., K.T., J.W., V.Y., D.X.D.Z., R.T.F., B.D.M.), Department of Medicinal Chemistry (M.M.W.), and Department of Pharmacokinetics and Drug Metabolism (X.B., V.B., J.R.), Amgen Inc., Cambridge, Massachusetts and Thousand Oaks, California

Potent and selective antagonists of the voltage-gated sodium channel Na1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human Na1.7 channels with an IC of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other Na family members, including Na1.4 expressed in muscle and Na1.5 expressed in the heart, as well as TTX-resistant Na channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple Na1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective Na1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.
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http://dx.doi.org/10.1124/jpet.116.239590DOI Listing
July 2017

Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.

ACS Med Chem Lett 2013 Dec 21;4(12):1218-23. Epub 2013 Oct 21.

Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.

Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.
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http://dx.doi.org/10.1021/ml4003315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027438PMC
December 2013

Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.

J Med Chem 2013 Dec 11;56(24):10003-15. Epub 2013 Dec 11.

Department of Chemistry Research and Discovery, ‡Department of Pharmacokinetics and Drug Metabolism, §Oncology Research, ∥Department of Molecular Structure, ⊥Bioassay and Profiling, and #Pharmaceutics, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.

Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
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http://dx.doi.org/10.1021/jm401317zDOI Listing
December 2013

Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors.

J Med Chem 2013 Jun 23;56(11):4320-42. Epub 2013 May 23.

Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.

Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
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http://dx.doi.org/10.1021/jm4000038DOI Listing
June 2013

Structure-Based Design of Potent and Selective CK1γ Inhibitors.

ACS Med Chem Lett 2012 Dec 18;3(12):1059-64. Epub 2012 Oct 18.

Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.

Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms. A single oral dose of compound 13 resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.
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http://dx.doi.org/10.1021/ml300278fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025826PMC
December 2012

Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor.

Bioorg Med Chem Lett 2008 Oct 29;18(20):5643-7. Epub 2008 Aug 29.

Department of Medicinal Chemistry, Amgen Inc., 1 Kendall Square, Building 1000, Cambridge, MA, USA.

The synthesis and structure-activity relationship of a series of carbamate potentiators of alpha4beta2 nAChR is reported herein. These compounds were highly selective for alpha4beta2 over other nAChR subtypes. In addition, compounds increased the response of alpha4beta2 nAChRs to acetylcholine, as measured with patch-clamp electrophysiology.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.092DOI Listing
October 2008

Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.

Bioorg Med Chem Lett 2008 Oct 28;18(19):5209-12. Epub 2008 Aug 28.

Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA, USA.

The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.080DOI Listing
October 2008

Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

J Med Chem 2008 Mar 7;51(6):1668-80. Epub 2008 Mar 7.

Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA.

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
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http://dx.doi.org/10.1021/jm701098wDOI Listing
March 2008