| Autor: |
Reiter LA; Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA., Subramanyam C, Mangual EJ, Jones CS, Smeets MI, Brissette WH, McCurdy SP, Lira PD, Linde RG, Li Q, Zhang F, Antipas AS, Blumberg LC, Doty JL, Driscoll JP, Munchhof MJ, Ripp SL, Shavnya A, Shepard RM, Sperger D, Thomasco LM, Trevena KA, Wolf-Gouveia LA, Zhang L |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2007 Oct 01; Vol. 17 (19), pp. 5447-54. Date of Electronic Publication: 2007 Jul 31. |
| DOI: |
10.1016/j.bmcl.2007.07.038 |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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