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Andrew Scribner,
Joseph A Moore,
Gilles Ouvry, Michael Fisher,
Matthew Wyvratt,
Penny Leavitt,
Paul Liberator,
Anne Gurnett,
Chris Brown,
John Mathew,
Donald Thompson,
Dennis Schmatz,
Tesfaye Biftu
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ABSTRACT: Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Bioorganic & medicinal chemistry letters 02/2009; 19(5):1517-21. · 2.65 Impact Factor
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Andrew Scribner,
Susan Meitz, Michael Fisher,
Matthew Wyvratt,
Penny Leavitt,
Paul Liberator,
Anne Gurnett,
Chris Brown,
John Mathew,
Donald Thompson,
Dennis Schmatz,
Tesfaye Biftu
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[hide abstract]
ABSTRACT: Novel 5,6-diarylimidazo[2,1-b][1,3]thiazoles bearing an amine substituent at the imidazothiazole 2-position have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 10.
Bioorganic & medicinal chemistry letters 09/2008; 18(19):5263-7. · 2.65 Impact Factor
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Andrew Scribner,
Richard Dennis,
Shuliang Lee,
Gilles Ouvry,
David Perrey, Michael Fisher,
Matthew Wyvratt,
Penny Leavitt,
Paul Liberator,
Anne Gurnett,
Chris Brown,
John Mathew,
Donald Thompson,
Dennis Schmatz,
Tesfaye Biftu
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[hide abstract]
ABSTRACT: Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
European Journal of Medicinal Chemistry 07/2008; 43(6):1123-51. · 3.35 Impact Factor
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Gui-Bai Liang,
Xiaoxia Qian,
Dennis Feng, Michael Fisher,
Tami Crumley,
Sandra J Darkin-Rattray,
Paula M Dulski,
Anne Gurnett,
Penny Sue Leavitt,
Paul A Liberator,
Andrew S Misura,
Samantha Samaras,
Tamas Tamas,
Dennis M Schmatz,
Matthew Wyvratt,
Tesfaye Biftu
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ABSTRACT: Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2019-22. · 2.65 Impact Factor
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Gui-Bai Liang,
Xiaoxia Qian,
Dennis Feng, Michael Fisher,
Christine M Brown,
Anne Gurnett,
Penny Sue Leavitt,
Paul A Liberator,
Andrew S Misura,
Tamas Tamas,
Dennis M Schmatz,
Matthew Wyvratt,
Tesfaye Biftu
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ABSTRACT: Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.
Bioorganic & Medicinal Chemistry Letters 08/2007; 17(13):3558-61. · 2.55 Impact Factor
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Dennis Feng, Michael Fisher,
Gui-Bai Liang,
Xiaoxia Qian,
Chris Brown,
Anne Gurnett,
Penny Sue Leavitt,
Paul A Liberator,
John Mathew,
Andrew Misura,
Samantha Samaras,
Tamas Tamas,
Dennis M Schmatz,
Matthew Wyvratt,
Tesfaye Biftu
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ABSTRACT: Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.
Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):5978-81. · 2.55 Impact Factor
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Xiaoxia Qian,
Gui-Bai Liang,
Dennis Feng, Michael Fisher,
Tami Crumley,
Sandra Rattray,
Paula M Dulski,
Anne Gurnett,
Penny Sue Leavitt,
Paul A Liberator,
Andrew S Misura,
Samantha Samaras,
Tamas Tamas,
Dennis M Schmatz,
Matthew Wyvratt,
Tesfaye Biftu
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[hide abstract]
ABSTRACT: 2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.
Bioorganic & Medicinal Chemistry Letters 06/2006; 16(10):2817-21. · 2.55 Impact Factor
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Tesfaye Biftu,
Dennis Feng, Michael Fisher,
Gui-Bai Liang,
Xiaoxia Qian,
Andrew Scribner,
Richard Dennis,
Shuliang Lee,
Paul A Liberator,
Chris Brown, [......],
Donald Thompson,
John Mathew,
Andrew Misura,
Samantha Samaras,
Tamas Tamas,
Joseph F Sina,
Kathleen A McNulty,
Crystal G McKnight,
Dennis M Schmatz,
Matthew Wyvratt
[show abstract]
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ABSTRACT: Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
Bioorganic & Medicinal Chemistry Letters 06/2006; 16(9):2479-83. · 2.55 Impact Factor
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Gui-Bai Liang,
Xiaoxia Qian,
Tesfaye Biftu,
Dennis Feng, Michael Fisher,
Tami Crumley,
Sandra J Darkin-Rattray,
Paula M Dulski,
Anne Gurnett,
Penny Sue Leavitt,
Paul A Liberator,
Andrew S Misura,
Samantha Samaras,
Tamas Tamas,
Dennis M Schmatz,
Matthew Wyvratt
[show abstract]
[hide abstract]
ABSTRACT: Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed.
Bioorganic & Medicinal Chemistry Letters 11/2005; 15(20):4570-3. · 2.55 Impact Factor
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Tesfaye Biftu,
Dennis Feng,
Mitree Ponpipom,
Narindar Girotra,
Gui-Bai Liang,
Xiaoxia Qian,
Robert Bugianesi,
Joseph Simeone,
Linda Chang,
Anne Gurnett, [......],
Terence Murphy,
Sandra Rattray,
Samantha Samaras,
Tamas Tamas,
John Mathew,
Christine Brown,
Don Thompson,
Dennis Schmatz, Michael Fisher,
Matthew Wyvratt
[show abstract]
[hide abstract]
ABSTRACT: Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
Bioorganic & Medicinal Chemistry Letters 08/2005; 15(13):3296-301. · 2.55 Impact Factor
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Andrew Scribner,
Richard Dennis,
Jean Hong,
Shuliang Lee,
Donald McIntyre,
David Perrey,
Dennis Feng, Michael Fisher,
Matthew Wyvratt,
Penny Leavitt,
Paul Liberator,
Anne Gurnett,
Chris Brown,
John Mathew,
Donald Thompson,
Dennis Schmatz,
Tesfaye Biftu
[show abstract]
[hide abstract]
ABSTRACT: Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
European Journal of Medicinal Chemistry 42(11-12):1334-57. · 3.35 Impact Factor
