Publications by authors named "Mark A Seefeld"

11 Publications

  • Page 1 of 1

Novel K7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction.

Bioorg Med Chem Lett 2018 12 29;28(23-24):3793-3797. Epub 2018 Sep 29.

Neuroscience Virtual-Proof-of-Concept Discovery Performance Unit, GlaxoSmithKline, Collegeville, PA, United States. Electronic address:

Neuronal voltage-gated potassium channels, K7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule K7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. K7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual K7 isoforms was investigated in human detrusor tissue using a panel of K7 openers with distinct activity profiles among K7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric K7.4 did not reduce detrusor contraction. This may suggest that the homomeric K7.4 channel plays a less significant role in bladder contraction and further investigation is needed.
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http://dx.doi.org/10.1016/j.bmcl.2018.09.036DOI Listing
December 2018

Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

PLoS One 2014 30;9(6):e100880. Epub 2014 Jun 30.

Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.

Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076210PMC
February 2015

Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.

Nat Chem Biol 2014 Mar 5;10(3):181-7. Epub 2014 Jan 5.

Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.
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http://dx.doi.org/10.1038/nchembio.1427DOI Listing
March 2014

Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors.

Bioorg Med Chem Lett 2009 Apr 27;19(8):2244-8. Epub 2009 Feb 27.

Oncology Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.

A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
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http://dx.doi.org/10.1016/j.bmcl.2009.02.094DOI Listing
April 2009

Aminofurazans as potent inhibitors of AKT kinase.

Bioorg Med Chem Lett 2009 Mar 9;19(5):1508-11. Epub 2009 Jan 9.

Oncology Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.

AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.
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http://dx.doi.org/10.1016/j.bmcl.2009.01.002DOI Listing
March 2009

Inhibitors of pantothenate kinase: novel antibiotics for staphylococcal infections.

Antimicrob Agents Chemother 2003 Jun;47(6):2051-5

Microbial, Musculoskeletal and Proliferative Diseases and Bioinformatics, GlaxoSmithKline Pharmaceuticals, Collegeville Pennsylvania 19426, USA.

Pantothenate kinase (CoaA) catalyzes the first step of the coenzyme A biosynthetic pathway. Here we report the identification of the Staphylococcus aureus coaA gene and characterization of the enzyme. We have also identified a series of low-molecular-weight compounds which are effective inhibitors of S. aureus CoaA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC155856PMC
http://dx.doi.org/10.1128/aac.47.6.2051-2055.2003DOI Listing
June 2003

Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.

J Med Chem 2003 Apr;46(9):1627-35

GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, Pennsylvania 19426, USA.

Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
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http://dx.doi.org/10.1021/jm0204035DOI Listing
April 2003

Defining and combating the mechanisms of triclosan resistance in clinical isolates of Staphylococcus aureus.

Antimicrob Agents Chemother 2002 Nov;46(11):3343-7

Microbial, Musculoskeletal and Proliferative Diseases CEDD. Computational and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.

The MICs of triclosan for 31 clinical isolates of Staphylococcus aureus were 0.016 micro g/ml (24 strains), 1 to 2 micro g/ml (6 strains), and 0.25 micro g/ml (1 strain). All the strains for which triclosan MICs were elevated (>0.016 micro g/ml) showed three- to fivefold increases in their levels of enoyl-acyl carrier protein (ACP) reductase (FabI) production. Furthermore, strains for which triclosan MICs were 1 to 2 micro g/ml overexpressed FabI with an F204C alteration. Binding studies with radiolabeled NAD(+) demonstrated that this change prevents the formation of the stable triclosan-NAD(+)-FabI complex, and both this alteration and its overexpression contributed to achieving MICs of 1 to 2 micro g/ml for these strains. Three novel, potent inhibitors of FabI (50% inhibitory concentrations, < or =64 nM) demonstrated up to 1,000-fold better activity than triclosan against the strains for which triclosan MICs were elevated. None of the compounds tested from this series formed a stable complex with NAD(+)-FabI. Consequently, although the overexpression of wild-type FabI gave rise to an increase in the MICs, as expected, overexpression of FabI with an F204C alteration did not cause an additional increase in resistance. Therefore, this work identifies the mechanisms of triclosan resistance in S. aureus, and we present three compounds from a novel chemical series of FabI inhibitors which have excellent activities against both triclosan-resistant and -sensitive clinical isolates of S. aureus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC128739PMC
http://dx.doi.org/10.1128/aac.46.11.3343-3347.2002DOI Listing
November 2002

Discovery of a novel and potent class of FabI-directed antibacterial agents.

Antimicrob Agents Chemother 2002 10;46(10):3118-24

Microbial, Musculoskeletal and Proliferative Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC128775PMC
http://dx.doi.org/10.1128/aac.46.10.3118-3124.2002DOI Listing
October 2002

Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).

J Med Chem 2002 Jul;45(15):3246-56

GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, PA 19426, USA.

Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.
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http://dx.doi.org/10.1021/jm020050+DOI Listing
July 2002

Convenient Asymmetric Syntheses of anti-beta-Amino Alcohols.

J Org Chem 1996 Apr;61(8):2677-2685

Imperial College of Science, Technology & Medicine, London SW7 2AY, England.

Condensation of allylborane reagents 9 and 12 with aldehydes gave anti-3-[(diphenylmethylene)amino]-1-alken-4-ols 10 and 13 with high relative and absolute stereocontrol. Subsequent deprotection gave the corresponding free anti-3-amino-1-alken-4-ols 11 and 14. Alternatively, reaction of imines 13a, 13f, and 13g with trifluoromethanesulfonic anhydride and acidic methanol gave, via rearrangement, double inversion, and hydrolysis, the isomeric anti-4-amino-1-alken-3-ols 22, 38a, and 38b in good yield. The stereochemistry of the rearrangement products has been established by a single crystal X-ray study of compound 37 and by chemical correlation.
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http://dx.doi.org/10.1021/jo9522062DOI Listing
April 1996