Steven B Hansel

Publications (5)13.46 Total impact

• Article: Utilization of in vitro Caco-2 permeability and liver microsomal half-life screens in discovering BMS-488043, a novel HIV-1 attachment inhibitor with improved pharmacokinetic properties.

  Zheng Yang, Lisa M Zadjura, Anthony M Marino, Celia J D'Arienzo, Jacek Malinowski, Christoph Gesenberg, Pin-Fang Lin, Richard J Colonno, Tao Wang, John F Kadow, Nicholas A Meanwell, Steven B Hansel
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  ABSTRACT: Optimizing pharmacokinetic properties to improve oral exposure is a common theme in modern drug discovery. In the present work, in vitro Caco-2 permeability and microsomal half-life screens were utilized in an effort to guide the structure-activity relationship in order to improve the pharmacokinetic properties of novel HIV-1 attachment inhibitors. The relevance of the in vitro screens to in vivo pharmacokinetic properties was first demonstrated with a number of program compounds at the early stage of lead optimization. The Caco-2 permeability, tested at 200 microM, was quantitatively predictive of in vivo oral absorption, with complete absorption occurring at a Caco-2 permeability of 100 nm/s or higher. The liver microsomal half-life screen, conducted at 1 microM substrate concentration, can readily differentiate low-, intermediate-, and high-clearance compounds in rats, with a nearly 1:1 correlation in 12 out of 13 program compounds tested. Among the >100 compounds evaluated, BMS-488043 emerged as a lead, exhibiting a Caco-2 permeability of 178 nm/s and a microsomal half-life predictive of a low clearance (4 mL/min/kg) in humans. These in vitro characteristics translated well to the in vivo setting. The oral bioavailability of BMS-488043 in rats, dogs, and monkeys was 90%, 57%, and 60%, respectively. The clearance was low in all three species tested, with a terminal half-life ranging from 2.4 to 4.7 h. Furthermore, the oral exposure of BMS-488043 was significantly improved (6- to 12-fold in rats and monkeys) compared to the prototype compound BMS-378806 that had a suboptimal Caco-2 permeability (51 nm/s) and microsomal half-life. More importantly, the improvements in preclinical pharmacokinetics translated well to humans, leading to a >15-fold increase in the human oral exposure of BMS-488043 than BMS-378806 and enabling a clinical proof-of-concept for this novel class of anti-HIV agents. The current studies demonstrated the valuable role of in vitro ADME screens in improving oral pharmacokinetics at the lead optimization stage.
  Journal of Pharmaceutical Sciences 09/2009; 99(4):2135-52. · 3.06 Impact Factor
• Article: Nitrogen-appended N-alkylsulfonamides as inhibitors of gamma-secretase.

  Carl P Bergstrom, Charles P Sloan, Henry H Wang, Michael F Parker, David W Smith, Ming Zheng, Steven B Hansel, Craig T Polson, Lauren E Barber, Isia Bursuker, Valerie L Guss, Jason A Corsa, Donna M Barten, Kevin M Felsenstein, Susan B Roberts
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  ABSTRACT: The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
  Bioorganic & medicinal chemistry letters 02/2008; 18(1):175-8. · 2.65 Impact Factor
• Article: Carbamate-appended N-alkylsulfonamides as inhibitors of gamma-secretase.

  Carl P Bergstrom, Charles P Sloan, Wai-Yu Lau, David W Smith, Ming Zheng, Steven B Hansel, Craig T Polson, Jason A Corsa, Donna M Barten, Kevin M Felsenstein, Susan B Roberts
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  ABSTRACT: The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
  Bioorganic & medicinal chemistry letters 02/2008; 18(2):464-8. · 2.65 Impact Factor
• Article: N-(5-chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gamma-secretase inhibitors.

  Michael F Parker, Donna M Barten, Carl P Bergstrom, Joanne J Bronson, Jason A Corsa, Milind S Deshpande, Kevin M Felsenstein, Valerie L Guss, Steven B Hansel, Graham Johnson, [......], Wai Y Lau, Jeremy Mock, C V C Prasad, Craig T Polson, Charles P Sloan, David W Smith, Owen B Wallace, Henry H Wang, Andrew Williams, Ming Zheng
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  ABSTRACT: A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
  Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4432-6. · 2.55 Impact Factor
• Article: Hydroxytriamides as potent gamma-secretase inhibitors.

  C V C Prasad, Owen B Wallace, Jeffrey W Noonan, Charles P Sloan, Wai Lau, Shikha Vig, Michael F Parker, David W Smith, Steven B Hansel, Craig T Polson, Donna M Barten, Kevin M Felsenstein, Susan B Roberts
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  ABSTRACT: Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.
  Bioorganic & Medicinal Chemistry Letters 04/2004; 14(8):1917-21. · 2.55 Impact Factor