Author/Authors :
Lawrence A. Reiter، نويسنده , , Chakrapani Subramanyam، نويسنده , , Emilio J. Mangual، نويسنده , , Christopher S. Jones، نويسنده , , Marc I. Smeets، نويسنده , , William H. Brissette، نويسنده , , Sandra P. McCurdy، نويسنده , , Paul D. Lira، نويسنده , , Robert G. Linde، نويسنده , , Qifang Li، نويسنده , , Fangning Zhang، نويسنده , , Amy S. Antipas، نويسنده , , Laura C. Blumberg، نويسنده , , Jonathan L. Doty، نويسنده , , James P. Driscoll، نويسنده , , Michael J. Munchhof، نويسنده , , Sharon L. Ripp، نويسنده , , Andrei Shavnya، نويسنده , , Richard M. Shepard، نويسنده , , Diana Sperger، نويسنده , , et al.، نويسنده ,
Abstract :
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.
Keywords :
thrombocytopenia , Low molecular weight agonist , Thrombopoietin , Small molecule agonist
