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Start Over Author "Kidambi A" Journal bioorganic & medicinal chemistry letters
27 results on '"Kidambi A"'

1. Amidines as amide bond replacements in VLA-4 antagonists

Author

Adria Colletti, Malcolm MacCoss, Theodore M. Kamenecka, Ermengilda McCauley, Linda A. Egger, Wei Tang, Sharon Tong, Usha Kidambi, Richard A. Mumford, Ralph A. Stearns, John A. Schmidt, You-Jung Park, Gail Van Riper, Linus S. Lin, Stephen E. de Laszlo, Yohannes Teffera, and William K. Hagmann

Subjects
Clinical Biochemistry, Cell, Integrin, Amidines, Pharmaceutical Science, Inflammation, Integrin alpha4beta1, Biochemistry, immune system diseases, Drug Discovery, medicine, Cell adhesion, Molecular Biology, biology, Cell adhesion molecule, Chemistry, Organic Chemistry, VLA-4, Amides, Small molecule, Extravasation, medicine.anatomical_structure, Area Under Curve, Immunology, Cancer research, biology.protein, Molecular Medicine, medicine.symptom
Abstract

VLA-4 (alpha(4)beta(1), very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biological evaluation of amidines as small molecule antagonists of VLA-4.

Published
2004

2. N-(3-Phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Author

Stephen E. de Laszlo, Clare E. Gutteridge, William K. Hagmann, Ermengilda McCauley, Usha Kidambi, Richard A. Mumford, Theodore M. Kamenecka, Linda A. Egger, Sharon Tong, and Gail Van Riper

Subjects
Stereochemistry, Phenylalanine, Carboxylic acid, Clinical Biochemistry, Integrin, Receptors, Lymphocyte Homing, Immunoglobulins, Vascular Cell Adhesion Molecule-1, Pharmaceutical Science, Integrin alpha4beta1, Biochemistry, Chemical synthesis, Inhibitory Concentration 50, Jurkat Cells, Radioligand Assay, Structure-Activity Relationship, Mucoproteins, Drug Discovery, Humans, Molecular Biology, Structural unit, chemistry.chemical_classification, biology, Chemistry, fungi, Organic Chemistry, Antagonist, VLA-4, Amides, In vitro, biology.protein, Molecular Medicine, Cell Adhesion Molecules
Abstract

The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N -(3-phenylsulfonyl-3-piperidinoyl)-( l )-4-(2′,6′-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC 50 =90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists.

Published
2003

3. Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists

Author

Richard A. Mumford, William K. Hagmann, Karen Owens, Plato A. Magriotis, Gail Van Riper, David N. Young, Ermengilda McCauley, Sharon Tong, Linus S. Lin, Usha Kidambi, Stephen E. deLaszlo, Ralph A. Stearns, John A. Schmidt, Adria Colletti, Yohannes Teffera, Kathryn A. Lyons, Malcolm MacCoss, Linda A. Egger, Dorothy Levorse, Thomas J. Lanza, Ihor E. Kopka, Stella H. Vincent, and Sander G. Mills

Subjects
Metabolic Clearance Rate, Stereochemistry, Clinical Biochemistry, Administration, Oral, Biological Availability, Vascular Cell Adhesion Molecule-1, Pharmaceutical Science, Peptide, Integrin alpha4beta1, Biochemistry, Chemical synthesis, Inhibitory Concentration 50, Jurkat Cells, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, Humans, Potency, Molecular Biology, chemistry.chemical_classification, Alanine, Dipeptide, Organic Chemistry, Blood proteins, In vitro, Sulfonamide, Bioavailability, chemistry, Molecular Medicine, Propionates, Protein Binding
Abstract

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-( l )-prolyl- and ( l )-azetidyl-β-biaryl β-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins.

Published
2002

4. N-Tetrahydrofuroyl-(l)-phenylalanine derivatives as potent VLA-4 antagonists

Author

John A. Schmidt, Plato A. Magriotis, Ermengilda McCauley, Usha Kidambi, George A. Doherty, Richard A. Mumford, Gail Van Riper, Linda L. Chang, Ginger X. Yang, Malcolm MacCoss, Stephen E. de Laszlo, William K. Hagmann, Quang Truong, Linda A. Egger, and Bing Li

Subjects
Stereochemistry, Phenylalanine, Clinical Biochemistry, Administration, Oral, Biological Availability, Vascular Cell Adhesion Molecule-1, Pharmaceutical Science, Integrin alpha4beta1, Biochemistry, Chemical synthesis, Phenylalanine derivatives, Rats, Sprague-Dawley, Inhibitory Concentration 50, Structure-Activity Relationship, Pharmacokinetics, immune system diseases, Oral administration, hemic and lymphatic diseases, Drug Discovery, Animals, Furans, Molecular Biology, Sulfonamides, Binding Sites, Dose-Response Relationship, Drug, Chemistry, Organic Chemistry, Antagonist, VLA-4, hemic and immune systems, respiratory system, Macaca mulatta, In vitro, Rats, Bioavailability, Molecular Medicine, Half-Life
Abstract

Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N -tetrahydrofuroyl-( l )-phenylalanine derivative ( 17 ) and related analogues as potent VLA-4 antagonists with good oral bioavailability.

Published
2002

5. Substituted N-(3,5-Dichlorobenzenesulfonyl)-l-prolyl-phenylalanine analogues as potent VLA-4 antagonists

Author

Plato A. Magriotis, John A. Schmidt, Stella H. Vincent, Junying Wang, Linus S. Lin, Dorothy Levorse, Sharon Tong, Zhen Wang, Linda E Egger, Ihor E. Kopka, Richard A. Mumford, Sander G. Mills, William K. Hagmann, Ralph A. Stearns, David N. Young, Malcolm MacCoss, Usha Kidambi, Ermengilda McCauley, Kathryn A. Lyons, Karen Owens, Gail Van Riper, Song Zheng, and Adria Colletti

Subjects
Metabolic Clearance Rate, Stereochemistry, Phenylalanine, Clinical Biochemistry, Biological Availability, Vascular Cell Adhesion Molecule-1, Pharmaceutical Science, Peptide, Integrin alpha4beta1, Ring (chemistry), Biochemistry, Chemical synthesis, Rats, Sprague-Dawley, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Dogs, Drug Discovery, Animals, Structure–activity relationship, Sulfones, Molecular Biology, IC50, chemistry.chemical_classification, Sheep, Dipeptide, Organic Chemistry, Dipeptides, Haplorhini, Rats, chemistry, Polar effect, Molecular Medicine
Abstract

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.

Published
2002

6. The discovery of small molecule carbamates as potent dual α4β1/α4β7 integrin antagonists

Author

Richard A. Mumford, Gail Van Riper, Kathryn A. Lyons, John A. Schmidt, William K. Hagmann, Malcolm MacCoss, Ermengilda McCauley, Usha Kidambi, Linda L. Chang, Linda A. Egger, Stella H. Vincent, and Quang Truong

Subjects
chemistry.chemical_classification, biology, Cell adhesion molecule, Chemistry, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Integrin, Pharmaceutical Science, Alpha (ethology), Peptide, Biochemistry, Small molecule, Drug Discovery, biology.protein, Molecular Medicine, Structure–activity relationship, Binding site, Beta (finance), Molecular Biology
Abstract

The alpha(4)beta(1) and alpha(4)beta(7) integrins are implicated in several inflammatory disease states. Systematic SAR studies of an alpha(4)beta(1)-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new alpha(4)beta(7) binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in alpha(4)beta(7) binding affinity while maintaining subnanomolar alpha(4)beta(1) activity, for example 2l, VCAM-Ig alpha(4)beta(1) IC(50)=0.13 nM, VCAM-Ig alpha(4)beta(7) IC(50)=1.92 nM.

Published
2002

7. Specific and dual antagonists of α4β1 and α4β7 integrins

Author

Malcolm MacCoss, John A. Schmidt, Linda A. Egger, Linus S. Lin, Jin Cao, Richard A. Mumford, Gail Van Riper, William K. Hagmann, Thomas J. Lanza, Usha Kidambi, and Ermenegilda McCauley

Subjects
chemistry.chemical_classification, Dipeptide, biology, Cell adhesion molecule, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Integrin, Antagonist, Pharmaceutical Science, Peptide, Biochemistry, Chemical synthesis, In vitro, chemistry.chemical_compound, chemistry, Drug Discovery, biology.protein, Molecular Medicine, Binding site, Molecular Biology
Abstract

N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the α4β1 integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of α4β1 and α4β7, and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for α4β1 and α4β7 is proposed to explain the structure–activity relationship.

Published
2002

8. The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists

Author

Linda L. Chang, Plato A. Magriotis, Theodore M. Kamenecka, John A. Schmidt, David N. Young, Ralph A. Stearns, Sharon Tong, Linda A. Egger, Philippe L. Durette, Adria Colletti, Ermengilda McCauley, Kathryn A. Lyons, Johannes Teffera, Richard A. Mumford, Jonathan E. Wilson, Stephen E. de Laszlo, Dorothy Levorse, Linus S. Lin, Judy Fenyk-Melody, Bing Li, Ginger X. Yang, Nancy J. Kevin, William K. Hagmann, Thomas J. Lanza, Malcolm MacCoss, Stella H. Vincent, Karen Owens, Gail Van Riper, Philip Kim, Ihor E. Kopka, Sander G. Mills, and Usha Kidambi

Subjects
Integrins, Metabolic Clearance Rate, Stereochemistry, Clinical Biochemistry, Receptors, Lymphocyte Homing, Biological Availability, Pharmaceutical Science, Peptide, Integrin alpha4beta1, Biochemistry, Chemical synthesis, Structure-Activity Relationship, chemistry.chemical_compound, Dogs, In vivo, Drug Discovery, Peptide synthesis, Animals, Molecular Biology, chemistry.chemical_classification, Dipeptide, Organic Chemistry, VLA-4, Dipeptides, Macaca mulatta, In vitro, Rats, Sulfonamide, chemistry, Molecular Medicine, Sulfonic Acids
Abstract

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

Published
2001

9. Amidines as amide bond replacements in VLA-4 antagonists

Author

Kamenecka, Theodore M, primary, Park, You-Jung, additional, Lin, Linus S, additional, de Laszlo, Stephen, additional, McCauley, Ermengilda D, additional, Van Riper, Gail, additional, Egger, Linda, additional, Kidambi, Usha, additional, Mumford, Richard A, additional, Tong, Sharon, additional, Tang, Wei, additional, Colletti, Adria, additional, Teffera, Yohannes, additional, Stearns, Ralph, additional, MacCoss, Malcolm, additional, Schmidt, John A, additional, and Hagmann, William K, additional

Published
2004
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11. Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists

Author

Kopka, Ihor E, primary, Lin, Linus S, additional, Mumford, Richard A, additional, Lanza, Thomas, additional, Magriotis, Plato A, additional, Young, David, additional, DeLaszlo, Stephen E, additional, MacCoss, Malcolm, additional, Mills, Sander G, additional, Van Riper, Gail, additional, McCauley, Ermengilda, additional, Lyons, Kathryn, additional, Vincent, Stella, additional, Egger, Linda A, additional, Kidambi, Usha, additional, Stearns, Ralph, additional, Colletti, Adria, additional, Teffera, Yohannes, additional, Tong, Sharon, additional, Owens, Karen, additional, Levorse, Dorothy, additional, Schmidt, John A, additional, and Hagmann, William K, additional

Published
2002
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12. N-Aryl-prolyl-dipeptides as potent antagonists of VLA-4

Author

Kamenecka, Theodore M., primary, Lanza, Jr., Thomas, additional, de Laszlo, Stephen E., additional, Li, Bing, additional, McCauley, Ermengilda D., additional, Van Riper, Gail, additional, Egger, Linda A., additional, Kidambi, Usha, additional, Mumford, Richard A., additional, Tong, Sharon, additional, MacCoss, Malcolm, additional, Schmidt, John A., additional, and Hagmann, William K., additional

Published
2002
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13. CorrigendumCorrigendum to “The discovery of acylated β-Amino acids as potent and orally bioavailable VLA-4 antagonists”[Bioorg. Med. Chem. Lett. 12 (2002) 611]

Author

Lin, Linus S, primary, Kopka, Ihor E, additional, Mumford, Richard A, additional, Magriotis, Plato A, additional, Lanza, Jr, Thomas, additional, Durette, Philippe L, additional, Kamenecka, Theodore, additional, Young, David N, additional, de Laszlo, Stephen E, additional, McCauley, Ermenegilda, additional, Van Riper, Gail, additional, Kidambi, Usha, additional, Egger, Linda A, additional, Tong, Xinchun, additional, Lyons, Kathryn, additional, Vincent, Stella, additional, Stearns, Ralph, additional, Colletti, Adria, additional, Teffera, Yohannes, additional, Fenyk-Melody, Judy, additional, Schmidt, John A, additional, MacCoss, Malcolm, additional, and Hagmann, William K, additional

Published
2002
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14. Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

Author

Doherty, George A., primary, Yang, Ginger X., additional, Borges, Edite, additional, Chang, Linda L., additional, MacCoss, Malcolm, additional, Tong, Sharon, additional, Kidambi, Usha, additional, Egger, Linda A., additional, McCauley, Ermenegilda, additional, Van Riper, Gail, additional, Mumford, Richard A., additional, Schmidt, John A., additional, and Hagmann, William K., additional

Published
2002
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15. N-Tetrahydrofuroyl-(l)-phenylalanine derivatives as potent VLA-4 antagonists

Author

Yang, Ginger X., primary, Chang, Linda L., additional, Truong, Quang, additional, Doherty, George A., additional, Magriotis, Plato A., additional, de Laszlo, Stephen E., additional, Li, Bing, additional, MacCoss, Malcolm, additional, Kidambi, Usha, additional, Egger, Linda A., additional, McCauley, Ermengilda, additional, Van Riper, Gail, additional, Mumford, Richard A., additional, Schmidt, John A., additional, and Hagmann, William K., additional

Published
2002
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16. The Discovery of acylated β-Amino acids as potent and orally bioavailable VLA-4 antagonists

Author

Lin, Linus S., primary, Kopka, Ihor E., additional, Mumford, Richard A., additional, Magriotis, Plato A., additional, Lanza, Thomas, additional, Durette, Philippe L., additional, Kamenecka, Theodore, additional, Young, David N., additional, Laszlo, Stephen E.de, additional, McCauley, Ermenegilda, additional, Riper, Gail Van, additional, Kidambi, Usha, additional, Egger, Linda A., additional, Tong, Xinchun, additional, Lyons, Kathryn, additional, Vincent, Stella, additional, Stearns, Ralph, additional, Colletti, Adria, additional, Teffera, Yohannes, additional, Fenyk-Melody, Judy, additional, Schmidt, John A., additional, MacCoss, Malcolm, additional, and Hagmann, William K., additional

Published
2002
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17. Substituted N-(3,5-Dichlorobenzenesulfonyl)-l-prolyl-phenylalanine analogues as potent VLA-4 antagonists

Author

Kopka, Ihor E, primary, Young, David N, additional, Lin, Linus S, additional, Mumford, Richard A, additional, Magriotis, Plato A, additional, MacCoss, Malcolm, additional, Mills, Sander G, additional, Riper, Gail Van, additional, McCauley, Ermengilda, additional, Egger, Linda E, additional, Kidambi, Usha, additional, Schmidt, John A, additional, Lyons, Kathryn, additional, Stearns, Ralph, additional, Vincent, Stella, additional, Colletti, Adria, additional, Wang, Zhen, additional, Tong, Sharon, additional, Wang, Junying, additional, Zheng, Song, additional, Owens, Karen, additional, Levorse, Dorothy, additional, and Hagmann, William K, additional

Published
2002
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18. Specific and dual antagonists of α4β1 and α4β7 integrins

Author

Lin, Linus S., primary, Lanza, Thomas, additional, McCauley, Ermenegilda, additional, Riper, Gail Van, additional, Kidambi, Usha, additional, Cao, Jin, additional, Egger, Linda A., additional, Mumford, Richard A., additional, Schmidt, John A., additional, MacCoss, Malcolm, additional, and Hagmann, William K., additional

Published
2002
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19. The discovery of small molecule carbamates as potent dual α4β1/α4β7 integrin antagonists

Author

Chang, Linda L., primary, Truong, Quang, additional, Mumford, Richard A., additional, Egger, Linda A., additional, Kidambi, Usha, additional, Lyons, Kathryn, additional, McCauley, Ermengilda, additional, Van Riper, Gail, additional, Vincent, Stella, additional, Schmidt, John A., additional, MacCoss, Malcolm, additional, and Hagmann, William K., additional

Published
2002
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20. The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists

Author

Hagmann, William K, primary, Durette, Philippe L, additional, Lanza, Thomas, additional, Kevin, Nancy Jo, additional, de Laszlo, Stephen E, additional, Kopka, Ihor E, additional, Young, David, additional, Magriotis, Plato A, additional, Li, Bing, additional, Lin, Linus S, additional, Yang, Ginger, additional, Kamenecka, Theodore, additional, Chang, Linda L, additional, Wilson, Jonathan, additional, MacCoss, Malcolm, additional, Mills, Sander G, additional, Van Riper, Gail, additional, McCauley, Ermengilda, additional, Egger, Linda A, additional, Kidambi, Usha, additional, Lyons, Kathryn, additional, Vincent, Stella, additional, Stearns, Ralph, additional, Colletti, Adria, additional, Teffera, Johannes, additional, Tong, Sharon, additional, Fenyk-Melody, Judy, additional, Owens, Karen, additional, Levorse, Dorothy, additional, Kim, Philip, additional, Schmidt, John A, additional, and Mumford, Richard A, additional

Published
2001
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21. CorrigendumCorrigendum to 'The discovery of acylated β-Amino acids as potent and orally bioavailable VLA-4 antagonists'[Bioorg. Med. Chem. Lett. 12 (2002) 611]

Author

Thomas J. Lanza, Plato A. Magriotis, Ralph A. Stearns, Malcolm MacCoss, Kathryn A. Lyons, Stella H. Vincent, Usha Kidambi, Adria Colletti, Linus S. Lin, Richard A. Mumford, Xinchun Tong, David N. Young, Stephen E. de Laszlo, Judy Fenyk-Melody, Ihor E. Kopka, John A. Schmidt, Philippe L. Durette, William K. Hagmann, Gail Van Riper, Ermenegilda McCauley, Yohannes Teffera, Theodore M. Kamenecka, and Linda A. Egger

Subjects
chemistry.chemical_classification, Biochemistry, Chemistry, Organic Chemistry, Clinical Biochemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, VLA-4, Molecular Biology, Amino acid, Bioavailability
Published
2002

26. <atl>Substituted N-(3,5-Dichlorobenzenesulfonyl)-l-prolyl-phenylalanine analogues as potent VLA-4 antagonists

Author

Kopka, Ihor E., Young, David N., Lin, Linus S., Mumford, Richard A., Magriotis, Plato A., MacCoss, Malcolm, Mills, Sander G., Riper, Gail Van, McCauley, Ermengilda, Egger, Linda E., Kidambi, Usha, Schmidt, John A., Lyons, Kathryn, Stearns, Ralph, Vincent, Stella, Colletti, Adria, Wang, Zhen, Tong, Sharon, Wang, Junying, and Zheng, Song

Subjects
*PHENYLALANINE, *PHARMACOKINETICS
Abstract

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-l-prolyl- and α-methyl-l-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50∼1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series. [Copyright &y& Elsevier]

Published
2002
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27. <atl>The Discovery of acylated β-Amino acids as potent and orally bioavailable VLA-4 antagonists

Author

Lin, Linus S., Kopka, Ihor E., Mumford, Richard A., Magriotis, Plato A., Lanza Jr., Thomas, Durette, Philippe L., Kamenecka, Theodore, Young, David N., Laszlo, Stephen E. de, McCauley, Ermenegilda, Riper, Gail Van, Kidambi, Usha, Egger, Linda A., Tong, Xinchun, Lyons, Kathryn, Vincent, Stella, Stearns, Ralph, Colletti, Adria, Teffera, Yohannes, and Fenyk-Melody, Judy

Subjects
*AMINO acids, *DRUG antagonism, *PHARMACOKINETICS
Abstract

Acylated β-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. [Copyright &y& Elsevier]

Published
2002
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