Pyrimidine benzamide-based thrombopoietin receptor agonists

Autor:	Diana Sperger, Laura Cook Blumberg, Emilio J. Mangual, Kristen A. Trevena, Christopher S. Jones, Jonathan L. Doty, Fangning Zhang, William H. Brissette, Marc I. Smeets, Qifang Li, Paul D. Lira, Amy S. Antipas, Lilli Ann Wolf-Gouveia, Sandra P. McCurdy, Lisa Marie Thomasco, Andrei Shavnya, Sharon L. Ripp, Richard M. Shepard, Liling Zhang, Chakrapani Subramanyam, Linde Robert Gerald, Michael John Munchhof, Lawrence A. Reiter, James P. Driscoll
Rok vydání:	2007
Předmět:	Pyrimidine Chemical Phenomena medicine.drug_class Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Carboxamide Antigens CD34 Cross Reactions Biochemistry Chemical synthesis Cell Line chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Humans Computer Simulation Thiazole Benzamide Molecular Biology Cell Proliferation Chemistry Physical Aryl Organic Chemistry Cell Differentiation Small molecule Molecular Weight Pyrimidines chemistry Solubility Benzamides Molecular Medicine Receptors Thrombopoietin
Zdroj:	Bioorganicmedicinal chemistry letters. 17(19)
ISSN:	0960-894X
Popis:	A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b28920ad58a16caa053bbc11c89c4ece https://pubmed.ncbi.nlm.nih.gov/17707640 Zobrazit plný text záznamu Full Text from ScienceDirect