A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs
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Research Article A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs Albert R. Cunningham,1, 2, 3 C. Alex Carrasquer,1, 3 and Donald R. Mattison2, 3 1 James
Graham Brown Cancer Center, University of Louisville, 529 S. Jackson Street, Louisville, KY 40202, USA of Medicine and Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA 2 Departments
Correspondence should be addressed to Albert R. Cunningham, [email protected] Received 29 July 2009; Accepted 18 September 2009 Recommended by Catherine Dinauer The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves’s disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action. Copyright © 2009 Albert R. Cunningham et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction Hyperthyroidism occurs in approximately 2/1000 pregnancies with the majority of those cases being Graves’ disease [1], an autoimmune disorder caused by TSHreceptor stimulating autoantibodies. Propylthiouracil (PTU) is the primary treatment of hyperthyroidism in the US followed by methimazole (MMI) while carbimazole (CMI) is not distributed in the US. Surgery and radioiodine are not recommended treatment modalities during pregnancy. Untreated hyperthyroidism during pregnancy leads to developmental toxicity which in
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