Gren Z Wang

Publications (10)25.76 Total impact

• Article: CCR2 receptor antagonists: optimization of biaryl sulfonamides to increase activity in whole blood.

  Gren Z Wang, Pamela A Haile, Tom Daniel, Benjamin Belot, Andrew Q Viet, Krista B Goodman, Deyou Sha, Sarah E Dowdell, Norbert Varga, Xuan Hong, [......], Alan Olzinski, Roberta Bernard, Christopher Evans, Amanda Emmons, Jacques Briand, Chun-Wa Chung, Ruben Quek, Dennis Lee, Peter J Gough, Clark A Sehon
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  ABSTRACT: A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.
  Bioorganic & medicinal chemistry letters 10/2011; 21(24):7291-4. · 2.65 Impact Factor
• Article: Potent, Selective and Orally Bioavailable Dihydropyrimidine Inhibitors of Rho Kinase (ROCK1) as Potential Therapeutic Agents for Cardiovascular Diseases

  Clark A. Sehon, Gren Z. Wang, Andrew Q. Viet, Krista B. Goodman, Sarah E. Dowdell, Patricia A. Elkins, Simon F. Semus, Christopher Evans, Larry J. Jolivette, Robert B. Kirkpatrick, Edward Dul, Sanjay S. Khandekar, Tracey Yi, Lois L. Wright, Gary K. Smith, David J. Behm, Ross Bentley, Christopher P. Doe, Erding Hu, Dennis Lee
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  ABSTRACT: Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.
  Journal of Medicinal Chemistry 10/2008; 51(21). · 4.80 Impact Factor
• Article: Aminomethylpiperazines as selective urotensin antagonists.

  Mark A Hilfiker, Daohua Zhang, Sarah E Dowdell, Krista B Goodman, John J McAtee, Jason W Dodson, Andrew Q Viet, Gren Z Wang, Clark A Sehon, David J Behm, Zining Wu, Luz H Carballo, Stephen A Douglas, Michael J Neeb
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  ABSTRACT: Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
  Bioorganic & medicinal chemistry letters 09/2008; 18(16):4470-3. · 2.65 Impact Factor
• Article: Development of potent and selective small-molecule human Urotensin-II antagonists.

  John J McAtee, Jason W Dodson, Sarah E Dowdell, Gerald R Girard, Krista B Goodman, Mark A Hilfiker, Clark A Sehon, Deyou Sha, Gren Z Wang, Ning Wang, [......], David J Behm, Luz H Carballo, Christopher A Evans, Harvey E Fries, Rakesh Nagilla, Theresa J Roethke, Xiaoping Xu, Catherine C K Yuan, Stephen A Douglas, Michael J Neeb
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  ABSTRACT: This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
  Bioorganic & medicinal chemistry letters 07/2008; 18(12):3500-3. · 2.65 Impact Factor
• Article: Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles.

  John J McAtee, Jason W Dodson, Sarah E Dowdell, Karl Erhard, Gerald R Girard, Krista B Goodman, Mark A Hilfiker, Jian Jin, Clark A Sehon, Deyou Sha, [......], Nambi V Aiyar, David J Behm, Luz H Carballo, Christopher A Evans, Harvey E Fries, Rakesh Nagilla, Theresa J Roethke, Xiaoping Xu, Stephen A Douglas, Michael J Neeb
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  ABSTRACT: Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
  Bioorganic & medicinal chemistry letters 07/2008; 18(13):3716-9. · 2.65 Impact Factor
• Article: Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications.

  Jennifer X Qiao, Tammy C Wang, Gren Z Wang, Daniel L Cheney, Kan He, Alan R Rendina, Baomin Xin, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.
  Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5041-8. · 2.55 Impact Factor
• Article: SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.

  Jennifer X Qiao, Chong-Hwan Chang, Daniel L Cheney, Paul E Morin, Gren Z Wang, Sarah R King, Tammy C Wang, Alan R Rendina, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.
  Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4419-27. · 2.55 Impact Factor
• Article: Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

  Krista B Goodman, Haifeng Cui, Sarah E Dowdell, Dimitri E Gaitanopoulos, Robert L Ivy, Clark A Sehon, Robert A Stavenger, Gren Z Wang, Andrew Q Viet, Weiwei Xu, [......], Sanjay S Khandekar, Tracey Yi, David K Jung, Lois L Wright, Gary K Smith, David J Behm, Ross Bentley, Christopher P Doe, Erding Hu, Dennis Lee
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  ABSTRACT: Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
  Journal of Medicinal Chemistry 02/2007; 50(1):6-9. · 5.25 Impact Factor
• Article: Development of potent and selective small-molecule human Urotensin-II antagonists

  John J. McAtee, Jason W. Dodson, Sarah E. Dowdell, Gerald R. Girard, Krista B. Goodman, Mark A. Hilfiker, Clark A. Sehon, Deyou Sha, Gren Z. Wang, Ning Wang, [......], David J. Behm, Luz H. Carballo, Christopher A. Evans, Harvey E. Fries, Rakesh Nagilla, Theresa J. Roethke, Xiaoping Xu, Catherine C.K. Yuan, Stephen A. Douglas, Michael J. Neeb
  Bioorganic & Medicinal Chemistry Letters. 18(12):3500-3503.
• Article: Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

  John J. McAtee, Jason W. Dodson, Sarah E. Dowdell, Karl Erhard, Gerald R. Girard, Krista B. Goodman, Mark A. Hilfiker, Jian Jin, Clark A. Sehon, Deyou Sha, [......], Nambi V. Aiyar, David J. Behm, Luz H. Carballo, Christopher A. Evans, Harvey E. Fries, Rakesh Nagilla, Theresa J. Roethke, Xiaoping Xu, Stephen A. Douglas, Michael J. Neeb
  Bioorganic & Medicinal Chemistry Letters. 18(13):3716-3719.