Doree Sitkoff

Publications (10)29.33 Total impact

• Article: Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors.

  Yan Shi, Stephen P O'Connor, Doree Sitkoff, Jing Zhang, Mengxiao Shi, Sharon N Bisaha, Ying Wang, Chi Li, Zheming Ruan, R Michael Lawrence, [......], Kevin Kish, Eddie C-K Liu, Steve M Seiler, Liang Schweizer, Thomas E Steinbacher, William A Schumacher, Jeffrey A Robl, John E Macor, Karnail S Atwal, Philip D Stein
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  ABSTRACT: The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.
  Bioorganic & medicinal chemistry letters 12/2011; 21(24):7516-21. · 2.65 Impact Factor
• Article: Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.

  Yan Shi, Chi Li, Stephen P O'Connor, Jing Zhang, Mengxiao Shi, Sharon N Bisaha, Ying Wang, Doree Sitkoff, Andrew T Pudzianowski, Christine Huang, Herbert E Klei, Kevin Kish, Joseph Yanchunas, Eddie C-K Liu, Karen S Hartl, Steve M Seiler, Thomas E Steinbacher, William A Schumacher, Karnail S Atwal, Philip D Stein
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  ABSTRACT: We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
  Bioorganic & medicinal chemistry letters 10/2009; 19(24):6882-9. · 2.65 Impact Factor
• Article: Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.

  Yan Shi, Jing Zhang, Mengxiao Shi, Stephen P O'Connor, Sharon N Bisaha, Chi Li, Doree Sitkoff, Andrew T Pudzianowski, Saeho Chong, Herbert E Klei, Kevin Kish, Joseph Yanchunas, Eddie C-K Liu, Karen S Hartl, Steve M Seiler, Thomas E Steinbacher, William A Schumacher, Karnail S Atwal, Philip D Stein
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  ABSTRACT: The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
  Bioorganic & medicinal chemistry letters 07/2009; 19(15):4034-41. · 2.65 Impact Factor
• Article: Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors⊥‡

  Yan Shi, Doree Sitkoff, Jing Zhang, Herbert E. Klei, Kevin Kish, Eddie C.-K. Liu, Karen S. Hartl, Steve M. Seiler, Ming Chang, Christine Huang, Sonia Youssef, Thomas E. Steinbacher, William A. Schumacher, Nyeemah Grazier, Andrew Pudzianowski, Atsu Apedo, Lorell Discenza, Joseph Yanchunas, Philip D. Stein, Karnail S. Atwal
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  ABSTRACT: An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC50 = 2.4 nM, EC2xPT = 1.2 μM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
  Journal of Medicinal Chemistry 11/2008; 51(23). · 4.80 Impact Factor
• Article: (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential.

  Saleem Ahmad, Cort S Madsen, Philip D Stein, Evan Janovitz, Christine Huang, Khehyong Ngu, Sharon Bisaha, Lawrence J Kennedy, Bang-Chi Chen, Rulin Zhao, [......], Van Nguyen-Tran, Carolyn A Cuff, Thomas Harrity, Celia J Darienzo, Tong Li, Richard A Reeves, Michael A Blanar, Joel C Barrish, Robert Zahler, Jeffrey A Robl
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  ABSTRACT: 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
  Journal of Medicinal Chemistry 06/2008; 51(9):2722-33. · 5.25 Impact Factor
• Article: Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors.

  Yan Shi, Doree Sitkoff, Jing Zhang, Wei Han, Zilun Hu, Philip D Stein, Ying Wang, Lawrence J Kennedy, Stephen P O'Connor, Saleem Ahmad, Eddie C-K Liu, Steve M Seiler, Patrick Y S Lam, Jeffrey A Robl, John E Macor, Karnail S Atwal, Robert Zahler
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  ABSTRACT: The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5952-8. · 2.55 Impact Factor
• Article: A comparative study of available software for high-accuracy homology modeling: from sequence alignments to structural models.

  Akbar Nayeem, Doree Sitkoff, Stanley Krystek
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  ABSTRACT: An open question in protein homology modeling is, how well do current modeling packages satisfy the dual criteria of quality of results and practical ease of use? To address this question objectively, we examined homology-built models of a variety of therapeutically relevant proteins. The sequence identities across these proteins range from 19% to 76%. A novel metric, the difference alignment index (DAI), is developed to aid in quantifying the quality of local sequence alignments. The DAI is also used to construct the relative sequence alignment (RSA), a new representation of global sequence alignment that facilitates comparison of sequence alignments from different methods. Comparisons of the sequence alignments in terms of the RSA and alignment methodologies are made to better understand the advantages and caveats of each method. All sequence alignments and corresponding 3D models are compared to their respective structure-based alignments and crystal structures. A variety of protein modeling software was used. We find that at sequence identities >40%, all packages give similar (and satisfactory) results; at lower sequence identities (<25%), the sequence alignments generated by Profit and Prime, which incorporate structural information in their sequence alignment, stand out from the rest. Moreover, the model generated by Prime in this low sequence identity region is noted to be superior to the rest. Additionally, we note that DSModeler and MOE, which generate reasonable models for sequence identities >25%, are significantly more functional and easier to use when compared with the other structure-building software.
  Protein Science 04/2006; 15(4):808-24. · 2.80 Impact Factor
• Article: Ketene aminal-based lactam derivatives as a novel class of orally active FXa inhibitors.

  Yan Shi, Jing Zhang, Philip D Stein, Mengxiao Shi, Stephen P O'Connor, Sharon N Bisaha, Chi Li, Karnail S Atwal, Gregory S Bisacchi, Doree Sitkoff, [......], Karen S Hartl, Steven M Seiler, Sonia Youssef, Thomas E Steinbacher, William A Schumacher, Alan R Rendina, Jeffrey M Bozarth, Tara L Peterson, Ge Zhang, Robert Zahler
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  ABSTRACT: N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
  Bioorganic & Medicinal Chemistry Letters 01/2006; 15(24):5453-8. · 2.55 Impact Factor
• Article: Initial Structure-Activity Relationships for a Caprolactam-based Series of Neutral Factor Xa Inhibitors: Lead Identification

  Gregory S. Bisacchi, Philip D. Stein, Jack Z. Gougoutas, Karen S. Hartl, R. M. Lawrence, Eddie Liu, Andrew Pudzianowski, William A. Schumacher, Doree Sitkoff, Thomas E. Steinbacher, James Sutton, Zhaoxiao Zhang, Steven M. Seiler
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  ABSTRACT: Caprolactam urea 1, identified as a weak Factor Xa inhibitor screening hit (IC50 = 16 μM), served as the starting point for a limited parallel-synthesis driven SAR study to improve potency. Remarkably, the corresponding thiourea analog 8c (IC50 = 0.11 μM) was 145-fold more potent against Factor Xa compared to 1. In general, caprolactam analogs containing a thiourea linker were significantly more potent than their corresponding urea counterparts, and it is hypothesized that this is partly due to a conformational preference of the thiourea linkage which facilitates binding of the terminal groups of the inhibitors to the Factor Xa S1/S4 pockets. Analog 8c was selective against a panel of related serine proteases. Upon intra-duodenal administration in rats, 8c dose-dependently increased prothrombin time ex vivo, and when dosed i.v., it demonstrated efficacy in a rat model of venous thrombosis. This thiourea lead series formed the basis for follow-on investigations to discover potent drug-like Factor Xa inhibitors using the caprolactam scaffold but employing suitable thiourea surrogates.
  Letters in Drug Design &amp Discovery 11/2005; 2(8):625-630. · 0.87 Impact Factor
• Article: Tryptamine and homotryptamine-based sulfonamides as potent and selective inhibitors of 15-lipoxygenase.

  David S Weinstein, Wen Liu, Zhengxiang Gu, Charles Langevine, Khehyong Ngu, Leena Fadnis, Donald W Combs, Doree Sitkoff, Saleem Ahmad, Shaobin Zhuang, Xing Chen, Feng-Lai Wang, Deborah A Loughney, Karnail S Atwal, Robert Zahler, John E Macor, Cort S Madsen, Natesan Murugesan
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  ABSTRACT: A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
  Bioorganic & Medicinal Chemistry Letters 04/2005; 15(5):1435-40. · 2.55 Impact Factor