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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 GTPĪ³S 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
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Krista B Goodman,
Michael J Bury,
Mui Cheung,
Maria A Cichy-Knight,
Sarah E Dowdell,
Allison K Dunn,
Dennis Lee,
Jeffrey A Lieby,
Michael L Moore,
Daryl A Scherzer, [......],
Dean E McNulty,
Roland S Annan,
Rosalie E Matico,
Benjamin K Schwartz,
John J Trill,
Thomas D Sweitzer,
Da-Yuan Wang,
Paul M Keller,
John A Krawiec,
Michael C Jaye
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ABSTRACT: Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.
Bioorganic & medicinal chemistry letters 12/2008; 19(1):27-30. · 2.65 Impact Factor
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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
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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
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ABSTRACT: A number of fluorinated 1-aryl-tetrahydrocyclopentapyrazoles were synthesized and their insecticidal activity was evaluated. Some of the fluorinated compounds had significant insecticidal properties.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1702-6. · 2.55 Impact Factor
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ABSTRACT: A convenient synthetic route to novel 4-arylpyrazoles is described. The potential for insecticidal activity through GABA channel blockage by this series of compounds, as well as their selectivity for insect versus mammalian receptors, are explored through in vitro and in vivo assays.
Bioorganic & Medicinal Chemistry Letters 11/2004; 14(19):4949-53. · 2.55 Impact Factor
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Bin Shao,
Sam Victory,
Victor I Ilyin,
R Richard Goehring,
Qun Sun,
Derk Hogenkamp,
Diane D Hodges,
Khondaker Islam, Deyou Sha,
Chongwu Zhang,
Phong Nguyen,
Silvia Robledo,
George Sakellaropoulos,
Richard B Carter
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ABSTRACT: In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Journal of Medicinal Chemistry 09/2004; 47(17):4277-85. · 5.25 Impact Factor
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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.
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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.
