Donn G Wishka

Publications (11)36.14 Total impact

• Article: Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections.

  Justin I Montgomery, Matthew F Brown, Usa Reilly, Loren M Price, Joseph A Abramite, Joel Arcari, Rose Barham, Ye Che, Jinshan Michael Chen, Seung Won Chung, [......], John O'Donnell, Robert Oliver, Joseph Penzien, Mark Plummer, Veerabahu Shanmugasundaram, Christy Thoma, Andrew P Tomaras, Daniel P Uccello, Alfin Vaz, Donn G Wishka
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  ABSTRACT: The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
  Journal of Medicinal Chemistry 02/2012; 55(4):1662-70. · 4.80 Impact Factor
• Article: Potent inhibitors of LpxC for the treatment of Gram-negative infections.

  Matthew F Brown, Usa Reilly, Joseph A Abramite, Joel T Arcari, Robert Oliver, Rose A Barham, Ye Che, Jinshan Michael Chen, Elizabeth M Collantes, Seung Won Chung, [......], Mark C Noe, John O'Donnell, Joseph Penzien, Mark S Plummer, Loren M Price, Veerabahu Shanmugasundaram, Christy Thoma, Daniel P Uccello, Joseph S Warmus, Donn G Wishka
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  ABSTRACT: In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
  Journal of Medicinal Chemistry 12/2011; 55(2):914-23. · 4.80 Impact Factor
• Article: An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives.

  Donn G Wishka, Marion Bédard, Katherine E Brighty, Richard A Buzon, Kathleen A Farley, Michael W Fichtner, Goss S Kauffman, Jaap Kooistra, Jason G Lewis, Hardwin O'Dowd, Ivan J Samardjiev, Brian Samas, Geeta Yalamanchi, Mark C Noe
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  ABSTRACT: To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.
  The Journal of Organic Chemistry 01/2011; 76(6):1937-40. · 4.45 Impact Factor
• Article: Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

  Thomas V Magee, Sharon L Ripp, Bryan Li, Richard A Buzon, Lou Chupak, Thomas J Dougherty, Steven M Finegan, Dennis Girard, Anne E Hagen, Michael J Falcone, [......], Gregory G Stone, Timothy J Strelevitz, Jianmin Sun, Amelia Tait-Kamradt, Alfin D N Vaz, David A Whipple, Daniel W Widlicka, Donn G Wishka, Joanna P Wolkowski, Mark E Flanagan
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  ABSTRACT: Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
  Journal of Medicinal Chemistry 09/2009; 52(23):7446-57. · 4.80 Impact Factor
• Article: Preparation of novel azabicyclic amines and α7 nicotinic acetylcholine receptor activity of derived aryl amides

  Daniel P. Walker, Brad A. Acker, E. Jon Jacobsen, Donn G. Wishka
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  ABSTRACT: Three new azabicyclic amines, namely exo-3-amino-1-azabicyclo[3.2.1]octane, 3-amino-1-azabicyclo-[3.2.2]nonane and exo-6-amino-8-azabicyclo[3.2.1]octane, have been designed and prepared as isosteres of 3-aminoquinuclidine. Aryl amides derived from each series were prepared and tested in an 7 nicotinic acetylcholine receptor assay as part of a drug discovery program to treat the cognitive deficits in schizophrenia. All new amides showed significant 7 nAChR activity and one series displayed potent 7 activity equal to the quinuclidine series.
  Journal of Heterocyclic Chemistry 03/2009; 45(1):247 - 257. · 1.22 Impact Factor
• Article: Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity.

  Brad A Acker, E Jon Jacobsen, Bruce N Rogers, Donn G Wishka, Steven C Reitz, David W Piotrowski, Jason K Myers, Mark L Wolfe, Vincent E Groppi, Bruce A Thornburgh, [......], Barbara A Olson, Laura Fitzgerald, Brian A Staton, Thomas J Raub, Michael Krause, Kai S Li, William E Hoffmann, Mihaly Hajos, Raymond S Hurst, Daniel P Walker
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  ABSTRACT: A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
  Bioorganic & medicinal chemistry letters 07/2008; 18(12):3611-5. · 2.65 Impact Factor
• Source

  Available from: Bruce N Rogers

  Article: Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.

  Daniel P Walker, Donn G Wishka, David W Piotrowski, Shaojuan Jia, Steven C Reitz, Karen M Yates, Jason K Myers, Tatiana N Vetman, Brandon J Margolis, E Jon Jacobsen, [......], Brian A Staton, Thomas J Raub, Mihaly Hajos, William E Hoffmann, Kai S Li, Nicole R Higdon, Theron M Wall, Raymond S Hurst, Erik H F Wong, Bruce N Rogers
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  ABSTRACT: A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
  Bioorganic & Medicinal Chemistry 01/2007; 14(24):8219-48. · 2.92 Impact Factor
• Article: Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.

  Donn G Wishka, Daniel P Walker, Karen M Yates, Steven C Reitz, Shaojuan Jia, Jason K Myers, Kirk L Olson, E Jon Jacobsen, Mark L Wolfe, Vincent E Groppi, [......], Stanley Franklin, Galen Carey, Lisa H Gold, Karen K Cook, Steven B Sands, Sabrina X Zhao, John R Soglia, Amit S Kalgutkar, Stephen P Arneric, Bruce N Rogers
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  ABSTRACT: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
  Journal of Medicinal Chemistry 08/2006; 49(14):4425-36. · 5.25 Impact Factor
• Article: Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens.

  Michael R Barbachyn, Gary J Cleek, Lester A Dolak, Stuart A Garmon, Joel Morris, Eric P Seest, Richard C Thomas, Dana S Toops, William Watt, Donn G Wishka, [......], Douglas Stapert, Betty H Yagi, Wade J Adams, Janice M Friis, J Gregory Slatter, James P Sams, Nancee L Oien, Matthew J Zaya, Larry C Wienkers, Michael A Wynalda
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  ABSTRACT: A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.
  Journal of Medicinal Chemistry 02/2003; 46(2):284-302. · 5.25 Impact Factor
• Article: Stereoselective Synthesis of Furo[2,3-c]pyridine Pyrimidine Thioethers, A New Class of Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

  Donn G. Wishka, David R. Graber, Eric P. Seest, Lester A. Dolak, Fusen Han, William Watt, Joel Morris
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  ABSTRACT: An efficient stereoselective total synthesis of the furo[2,3-c]pyridine thiopyrimidine HIV-1 reverse transcriptase inhibitors, PNU-142721 and PNU-109886, has been developed. A convergent approach was utilized, providing direct access to the desired (S)-configuration of the molecule by making use of the alkylation of 4-amino-6-chloro-2-thiopyrimidine with the appropriate (R)-1-chloroethyl furo[2,3-c]pyridine intermediates. The successful preparation makes use of an efficient enzymatic kinetic resolution of the key 1-hydroxyethyl furo[2,3-c]pyridine intermediates to establish stereochemical control of the respective stereogenic centers. In addition, a workable asymmetric reduction strategy was developed for the synthesis of PNU-109886. Prudent reagent selection for the chlorination required for the final coupling reactions allowed for maintenance of the stereochemical integrity of the target compounds. Structural assignment of the absolute configuration of PNU-142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallographic analysis.
  10/1998;
• Article: (−)-6-Chloro-2-[(1-furo[2,3-c]pyridin-5-ylethyl)thio]-4-pyrimidinamine, PNU-142721, a New Broad Spectrum HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor

  Donn G. Wishka, David R. Graber, Laurice A. Kopta, Robert A. Olmsted, Janice M. Friis, John D. Hosley, Wade J. Adams, Eric P. Seest, Thomas M. Castle, Lester A. Dolak, [......], Fusen Han, William Watt, Wendy L. White, Toni-Jo Poel, Richard C. Thomas, Richard L. Voorman, Kevin J. Stefanski, Randall G. Stehle, W. Gary Tarpley, Joel Morris
  04/1998;