Discovery and SAR of 6-Alkyl-2,4-diaminopyrimidines as Histamine H4 Receptor Antagonists
| Autor: | Michael D. Hack, Brad M. Savall, Kevin Tays, Paul J. Dunford, Jeffery M. Cowden, Ronald L. Wolin, James P. Edwards, Frank Chavez, Robin L. Thurmond |
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| Rok vydání: | 2014 |
| Předmět: |
chemistry.chemical_classification
medicine.drug_class Drug discovery Phases of clinical research Carboxamide Pharmacology chemistry.chemical_compound chemistry Drug Discovery medicine Molecular Medicine Structure–activity relationship Histamine H4 receptor Histamine Tricyclic JNJ-7777120 medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 57:2429-2439 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects. |
| Databáze: | OpenAIRE |
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