Barbara A Schweitzer

Publications (6)15.71 Total impact

• Article: Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: identification of 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds.

  Marvin J Meyers, Scott A Long, Matthew J Pelc, Jane L Wang, Scott J Bowen, Mark C Walker, Barbara A Schweitzer, Heather M Madsen, Ruth E Tenbrink, Joseph McDonald, Sarah E Smith, Susan Foltin, David Beidler, Atli Thorarensen
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  ABSTRACT: Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.
  Bioorganic & medicinal chemistry letters 08/2011; 21(21):6538-44. · 2.65 Impact Factor
• Article: Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.

  Marvin J Meyers, Scott A Long, Matthew J Pelc, Jane L Wang, Scott J Bowen, Barbara A Schweitzer, Mark V Wilcox, Joseph McDonald, Sarah E Smith, Susan Foltin, Jeanne Rumsey, Young-Sun Yang, Mark C Walker, Satwik Kamtekar, David Beidler, Atli Thorarensen
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  ABSTRACT: Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.
  Bioorganic & medicinal chemistry letters 08/2011; 21(21):6545-53. · 2.65 Impact Factor
• Article: Structure based design of novel irreversible FAAH inhibitors.

  Jane L Wang, Scott J Bowen, Barbara A Schweitzer, Heather M Madsen, Joseph McDonald, Matthew J Pelc, Ruth E Tenbrink, David Beidler, Atli Thorarensen
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  ABSTRACT: Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.
  Bioorganic & medicinal chemistry letters 10/2009; 19(20):5970-4. · 2.65 Impact Factor
• Article: Thienopyrimidine-based P2Y12 platelet aggregation inhibitors.

  Steven W Kortum, Rhonda M Lachance, Barbara A Schweitzer, Gopichand Yalamanchili, Hayat Rahman, Michael D Ennis, Rita M Huff, Ruth E TenBrink
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  ABSTRACT: Herein we describe the design and synthesis of a novel series of potent thienopyrimidine P2Y12 inhibitors and the negative impact protein binding has on the inhibition of platelet aggregation.
  Bioorganic & medicinal chemistry letters 10/2009; 19(20):5919-23. · 2.65 Impact Factor
• Article: Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.

  Barbara A Schweitzer, William L Neumann, Hayat K Rahman, Carrie L Kusturin, Kirby R Sample, Gennadiy I Poda, Ravi G Kurumbail, Anna M Stevens, Roderick A Stegeman, William C Stallings, Michael S South
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  ABSTRACT: We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.
  Bioorganic & Medicinal Chemistry Letters 07/2005; 15(12):3006-11. · 2.55 Impact Factor
• Article: Discovery of imidazole glycerol phosphate dehydratase inhibitors through 3-D database searching.

  Barbara A Schweitzer, Paul J Loida, Claire A CaJacob, Robert C Chott, Elizabeth M Collantes, Shridhar G Hegde, Philip D Mosier, Salvatore Profeta
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  ABSTRACT: Imidazole glycerol phosphate dehydratase (IGPD) has become an attractive target for herbicide discovery since it is present in plants and not in mammals. Currently no knowledge is available on the 3-D structure of the IGPD active site. Therefore, we used a pharmacophore model based on known inhibitors and 3-D database searches to identify new active compounds. In vitro testing of compounds from the database searches led to the identification of a class of pyrrole aldehydes as novel inhibitors of IGPD.
  Bioorganic & Medicinal Chemistry Letters 08/2002; 12(13):1743-6. · 2.55 Impact Factor