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Your search keyword '"Kasireddy-Polam, P."' showing total 6 results
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6 results on '"Kasireddy-Polam, P."'

1. Dihydropyridopyrazinones and Dihydropteridinones as Corticotropin-Releasing Factor-1 Receptor Antagonists:  Structure−Activity Relationships and Computational Modeling.

Author

Carolyn D. Dzierba, Andrew J. Tebben, Richard G. Wilde, Amy G. Takvorian, Maria Rafalski, Padmaja Kasireddy-Polam, John D. Klaczkiewicz, Anthony D. Pechulis, Amy L. Davis, Mark P. Sweet, Alex M. Woo, Zhicai Yang, Sarah M. Ebeltoft, Thaddeus F. Molski, Ge Zhang, Robert C. Zaczek, George L. Trainor, Andrew P. Combs, and Paul J. Gilligan

Published
2007
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2. Synthesis, Structure−Activity Relationships, and in Vivo Properties of 3,4-Dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as Corticotropin-Releasing Factor-1 Receptor Antagonists

Author

Dzierba1, C. D., Takvorian, A. G., Rafalski, M., Kasireddy-Polam, P., Wong, H., Molski, T. F., Zhang, G., Li, Y.-W., Lelas, S., Peng, Y., McElroy, J. F., Zaczek, R. C., Taub, R. A., Combs, A. P., Gilligan, P. J., and Trainor, G. L.

Abstract

Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus−pituitary−adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.

Published
2004

3. Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists.

Author

Dzierba CD, Sielecki TM, Arvanitis AG, Galka A, Johnson TL, Takvorian AG, Rafalski M, Kasireddy-Polam P, Vig S, Dasgupta B, Zhang G, Molski TF, Wong H, Zaczek RC, Lodge NJ, Combs AP, Gilligan PJ, Trainor GL, Bronson JJ, and Macor JE

Subjects
Animals, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents chemistry, Anti-Anxiety Agents pharmacokinetics, Half-Life, Pteridines chemical synthesis, Pteridines pharmacokinetics, Pyrazines chemical synthesis, Pyrazines pharmacokinetics, Rats, Receptors, Corticotropin-Releasing Hormone metabolism, Structure-Activity Relationship, Pteridines chemistry, Pyrazines chemistry, Receptors, Corticotropin-Releasing Hormone antagonists & inhibitors
Abstract

Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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4. Dihydropyridopyrazinones and dihydropteridinones as corticotropin-releasing factor-1 receptor antagonists: structure-activity relationships and computational modeling.

Author

Dzierba CD, Tebben AJ, Wilde RG, Takvorian AG, Rafalski M, Kasireddy-Polam P, Klaczkiewicz JD, Pechulis AD, Davis AL, Sweet MP, Woo AM, Yang Z, Ebeltoft SM, Molski TF, Zhang G, Zaczek RC, Trainor GL, Combs AP, and Gilligan PJ

Subjects
Animals, Choroid Plexus metabolism, Frontal Lobe metabolism, In Vitro Techniques, Pteridines chemistry, Pteridines pharmacology, Pyridazines chemistry, Pyridazines pharmacology, Radioligand Assay, Rats, Receptors, Corticotropin-Releasing Hormone metabolism, Swine, Models, Molecular, Pteridines chemical synthesis, Pyridazines chemical synthesis, Quantitative Structure-Activity Relationship, Receptors, Corticotropin-Releasing Hormone antagonists & inhibitors
Abstract

The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.

Published
2007
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5. Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.

Author

Thompson LA, Liauw AY, Ramanjulu MM, Kasireddy-Polam P, Mercer SE, Maduskuie TP, Glicksman M, Roach AH, Meredith JE, Liu RQ, Combs AP, Higaki JN, Cordell B, Seiffert D, Zaczek RC, Robertson DW, and Olson RE

Subjects
Alzheimer Disease drug therapy, Alzheimer Disease enzymology, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Caprolactam analogs & derivatives, Cell Line, Dogs, Drug Design, Drug Evaluation, Preclinical, Endopeptidases chemistry, Enzyme Inhibitors chemistry, Humans, Molecular Conformation, Stereoisomerism, Structure-Activity Relationship, Caprolactam chemistry, Endopeptidases drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Succinates chemistry
Abstract

The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.

Published
2006
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6. Synthesis, structure-activity relationships, and in vivo properties of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as corticotropin-releasing factor-1 receptor antagonists.

Author

Dzierba CD, Takvorian AG, Rafalski M, Kasireddy-Polam P, Wong H, Molski TF, Zhang G, Li YW, Lelas S, Peng Y, McElroy JF, Zaczek RC, Taub RA, Combs AP, Gilligan PJ, and Trainor GL

Subjects
Administration, Oral, Animals, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents pharmacokinetics, Anti-Anxiety Agents pharmacology, Anxiety psychology, Behavior, Animal drug effects, Binding, Competitive, Dogs, Frontal Lobe drug effects, Frontal Lobe metabolism, Half-Life, In Vitro Techniques, Male, Pyrazines pharmacokinetics, Pyrazines pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Reaction Time drug effects, Receptors, Corticotropin-Releasing Hormone metabolism, Structure-Activity Relationship, Pyrazines chemical synthesis, Pyridines chemical synthesis, Receptors, Corticotropin-Releasing Hormone antagonists & inhibitors
Abstract

Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.

Published
2004
Full Text
View/download PDF

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