Mary Beth Young

Publications (10)34.83 Total impact

• Article: Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.

  Dai-Shi Su, John J Lim, Elizabeth Tinney, Thomas J Tucker, Sandeep Saggar, John T Sisko, Bang-Lin Wan, Mary Beth Young, Kenneth D Anderson, Deanne Rudd, [......], Gregory Moyer, Daniel J Distefano, Jessica A Flynn, Yuexia Liang, Rosa Sanchez, Rebecca Perlow-Poehnelt, Mike Miller, Joe P Vacca, Theresa M Williams, Neville J Anthony
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  ABSTRACT: Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4328-32. · 2.65 Impact Factor
• Article: SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.

  Hemaka A Rajapakse, Philippe G Nantermet, Harold G Selnick, James C Barrow, Georgia B McGaughey, Sanjeev Munshi, Stacey R Lindsley, Mary Beth Young, Phung L Ngo, M Katherine Holloway, [......], Beth Pietrak, Ming-Chih Crouthamel, Katherine Tugusheva, Qian Huang, Min Xu, Adam J Simon, Lawrence Kuo, Daria J Hazuda, Samuel Graham, Joseph P Vacca
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  ABSTRACT: The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
  Bioorganic & medicinal chemistry letters 02/2010; 20(6):1885-9. · 2.65 Impact Factor
• Article: Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.

  Dai-Shi Su, John J Lim, Elizabeth Tinney, Bang-Lin Wan, Mary Beth Young, Kenneth D Anderson, Deanne Rudd, Vandna Munshi, Carolyn Bahnck, Peter J Felock, [......], Gregory Moyer, Daniel J DiStefano, Jessica A Flynn, Yuexia Liang, Rosa Sanchez, Rebecca Perlow-Poehnelt, Mike Miller, Joe P Vacca, Theresa M Williams, Neville J Anthony
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  ABSTRACT: Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.
  Journal of Medicinal Chemistry 11/2009; 52(22):7163-9. · 4.80 Impact Factor
• Article: Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants.

  Dai-Shi Su, John J Lim, Elizabeth Tinney, Bang-Lin Wan, Mary Beth Young, Kenneth D Anderson, Deanne Rudd, Vandna Munshi, Carolyn Bahnck, Peter J Felock, [......], Yuexia Liang, Rosa Sanchez, Sridhar Prasad, Youwei Yan, Rebecca Perlow-Poehnelt, Maricel Torrent, Mike Miller, Joe P Vacca, Theresa M Williams, Neville J Anthony
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  ABSTRACT: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
  Bioorganic & medicinal chemistry letters 08/2009; 19(17):5119-23. · 2.65 Impact Factor
• Article: The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and D-serine.

  Sean M Smith, Jason M Uslaner, Lihang Yao, Chadwick M Mullins, Nathan O Surles, Sarah L Huszar, Caitlyn H McNaughton, Danette M Pascarella, Monika Kandebo, Richard M Hinchliffe, Tim Sparey, Nicholas J Brandon, Brian Jones, Shankar Venkatraman, Mary Beth Young, Nancy Sachs, Marlene A Jacobson, Peter H Hutson
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  ABSTRACT: Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.
  Journal of Pharmacology and Experimental Therapeutics 12/2008; 328(3):921-30. · 3.83 Impact Factor
• Article: The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.

  Tim Sparey, Pravien Abeywickrema, Sarah Almond, Nick Brandon, Noel Byrne, Alister Campbell, Pete H Hutson, Marlene Jacobson, Brian Jones, Sanjeev Munshi, Danette Pascarella, Andrew Pike, G Sridhar Prasad, Nancy Sachs, Melanie Sakatis, Vinod Sardana, Shankar Venkatraman, Mary Beth Young
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  ABSTRACT: The 'NMDA hypofunction hypothesis of schizophrenia' can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARs of 1.
  Bioorganic & medicinal chemistry letters 07/2008; 18(11):3386-91. · 2.65 Impact Factor
• Article: Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.

  Stacey R Lindsley, Keith P Moore, Hemaka A Rajapakse, Harold G Selnick, Mary Beth Young, Hong Zhu, Sanjeev Munshi, Lawrence Kuo, Georgia B McGaughey, Dennis Colussi, [......], Eric A Price, Sethu Sankaranarayanan, Adam J Simon, Guy R Seabrook, Daria J Hazuda, Nicole T Pudvah, Jerome H Hochman, Samuel L Graham, Joseph P Vacca, Philippe G Nantermet
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  ABSTRACT: This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
  Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):4057-61. · 2.55 Impact Factor
• Article: Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).

  Hemaka A Rajapakse, Philippe G Nantermet, Harold G Selnick, Sanjeev Munshi, Georgia B McGaughey, Stacey R Lindsley, Mary Beth Young, Ming-Tain Lai, Amy S Espeseth, Xiao-Ping Shi, [......], Beth Pietrak, Ming-Chih Crouthamel, Katherine Tugusheva, Qian Huang, Min Xu, Adam J Simon, Lawrence Kuo, Daria J Hazuda, Samuel Graham, Joseph P Vacca
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  ABSTRACT: We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
  Journal of Medicinal Chemistry 01/2007; 49(25):7270-3. · 5.25 Impact Factor
• Article: Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.

  Mary Beth Young, James C Barrow, Kristen L Glass, George F Lundell, Christina L Newton, Janetta M Pellicore, Kenneth E Rittle, Harold G Selnick, Kenneth J Stauffer, Joseph P Vacca, [......], S Dale Lewis, Bobby J Lucas, Daniel R McMasters, Cynthia Miller-Stein, Beth L Pietrak, Audrey A Wallace, Rebecca B White, Bradley Wong, Youwei Yan, Philippe G Nantermet
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  ABSTRACT: In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
  Journal of Medicinal Chemistry 07/2004; 47(12):2995-3008. · 5.25 Impact Factor
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  Article: Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors.

  Mark E Fraley, Kenneth L Arrington, Scott R Hambaugh, William F Hoffman, April M Cunningham, Mary Beth Young, Randall W Hungate, Andrew J Tebben, Ruth Z Rutledge, Richard L Kendall, William R Huckle, Rosemary C McFall, Kathleen E Coll, Kenneth A Thomas
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  ABSTRACT: We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
  Bioorganic & Medicinal Chemistry Letters 10/2003; 13(18):2973-6. · 2.55 Impact Factor