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Your search keyword '"Lorna Helen Mitchell"' showing total 2 results
Start Over Author "Lorna Helen Mitchell" Journal journal of medicinal chemistry
2 results on '"Lorna Helen Mitchell"'

1. Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery

Author

Kristin Lin, Kevin Sun, Guang Wei Lu, Felicity Grzemski, Lorna Helen Mitchell, Julie Spence, Lain-Yen Hu, Karen Elaine Sexton, Veerabahu Shanmugasundaram, Theodore R. Johnson, Daniel Du, Kim Wade, Neil Raheja, Kaushik Datta, David Pocalyko, Catherine R. Kostlan, and Zhi Wang

Subjects
Male, medicine.medical_specialty, Chemical Phenomena, Drug-Related Side Effects and Adverse Reactions, Administration, Topical, Sebum production, Hamster, Pharmacology, Internal medicine, Cricetinae, Drug Discovery, Follicular phase, Nitriles, medicine, Androgen Receptor Antagonists, Androgen receptor antagonist, Animals, Humans, biology, Mesocricetus, Chemistry, Rational design, Hair follicle, biology.organism_classification, Sebum, medicine.anatomical_structure, Endocrinology, Drug Design, Molecular Medicine, Hair Follicle
Abstract

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

Published
2010

2. 4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution

Author

William A. Denny, Alan J. Kraker, Brian D. Palmer, Lorna Helen Mitchell, R. John Booth, Leesa M Swan, Andrew M. Thompson, Ellen M. Dobrusin, Ho H. Lee, Daniel F. Ortwine, Jeff B. Smaill, and Elizabeth A. Lunney

Subjects
Models, Molecular, Stereochemistry, Carbazoles, Cell Cycle Proteins, Crystallography, X-Ray, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Benzene Derivatives, Structure–activity relationship, Humans, Pyrroles, CHEK1, chemistry.chemical_classification, biology, Carbazole, Kinase, Nuclear Proteins, Protein-Tyrosine Kinases, Wee1, Enzyme, chemistry, Checkpoint Kinase 1, biology.protein, Molecular Medicine, Signal transduction, Tyrosine kinase, Protein Kinases, Protein Binding
Abstract

High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

Published
2006

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