Eric A Wadman

Publications (7)20.76 Total impact

• Article: From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part II: Acyclic replacements for the (3S)-3-benzylpiperidine in a series of potent CCR3 antagonists.

  Daniel S Gardner, Joseph B Santella, Andrew J Tebben, Douglas G Batt, Soo S Ko, Sarah C Traeger, Patricia K Welch, Eric A Wadman, Paul Davies, Percy H Carter, John V Duncia
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  ABSTRACT: Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.
  Bioorganic & medicinal chemistry letters 02/2008; 18(2):586-95. · 2.65 Impact Factor
• Article: From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis.

  Joseph B Santella, Daniel S Gardner, Wenqing Yao, Chongsheng Shi, Prabhakar Reddy, Andrew J Tebben, George V DeLucca, Dean A Wacker, Paul S Watson, Patricia K Welch, [......], Paul Davies, Kimberly A Solomon, Dani M Graden, Swamy Yeleswaram, Sandhya Mandlekar, Ilona Kariv, Carl P Decicco, Soo S Ko, Percy H Carter, John V Duncia
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  ABSTRACT: Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
  Bioorganic & medicinal chemistry letters 02/2008; 18(2):576-85. · 2.65 Impact Factor
• Article: CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.

  James R Pruitt, Douglas G Batt, Dean A Wacker, Lori L Bostrom, Shon K Booker, Erin McLaughlin, Gregory C Houghton, Jeffrey G Varnes, David D Christ, Maryanne Covington, [......], Nicole C Stowell, Krishna G Vaddi, Eric A Wadman, Patricia K Welch, Swamy Yeleswaram, Kimberly A Solomon, Robert C Newton, Carl P Decicco, Percy H Carter, Soo S Ko
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  ABSTRACT: DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.
  Bioorganic & Medicinal Chemistry Letters 07/2007; 17(11):2992-7. · 2.55 Impact Factor
• Article: 2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: synthesis and selectivity.

  Paul S Watson, Bin Jiang, Kim Harrison, Nao Asakawa, Patricia K Welch, Maryanne Covington, Nicole C Stowell, Eric A Wadman, Paul Davies, Kimberly A Solomon, Robert C Newton, George L Trainor, Steven M Friedman, Carl P Decicco, Soo S Ko
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  ABSTRACT: Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(21):5695-9. · 2.55 Impact Factor
• Article: Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.

  George V De Lucca, Ui Tae Kim, Brian J Vargo, John V Duncia, Joseph B Santella, Daniel S Gardner, Changsheng Zheng, Ann Liauw, Zhang Wang, George Emmett, [......], Eric A Wadman, Anuk M Das, Paul Davies, Swamy Yeleswaram, Danielle M Graden, Kimberly A Solomon, Robert C Newton, George L Trainor, Carl P Decicco, Soo S Ko
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  ABSTRACT: Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
  Journal of Medicinal Chemistry 04/2005; 48(6):2194-211. · 5.25 Impact Factor
• Article: N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists.

  Douglas G Batt, Gregory C Houghton, John Roderick, Joseph B Santella, Dean A Wacker, Patricia K Welch, Yevgeniya I Orlovsky, Eric A Wadman, James M Trzaskos, Paul Davies, Carl P Decicco, Percy H Carter
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  ABSTRACT: The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.
  Bioorganic & Medicinal Chemistry Letters 03/2005; 15(3):787-91. · 2.55 Impact Factor
• Article: CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.

  Dean A Wacker, Joseph B Santella, Daniel S Gardner, Jeffrey G Varnes, Melissa Estrella, George V DeLucca, Soo S Ko, Keiichi Tanabe, Paul S Watson, Patricia K Welch, Maryanne Covington, Nicole C Stowell, Eric A Wadman, Paul Davies, Kimberly A Solomon, Robert C Newton, George L Trainor, Steven M Friedman, Carl P Decicco, John V Duncia
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  ABSTRACT: CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
  Bioorganic & Medicinal Chemistry Letters 08/2002; 12(13):1785-9. · 2.55 Impact Factor