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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Reiter LA,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 LMdoi
10.1016/j.bmcl.2007.07.038subject
Has Abstractpub_date
2007-10-01 00:00:00pages
5447-54issue
19eissn
0960-894Xissn
1464-3405pii
S0960-894X(07)00839-6journal_volume
17pub_type
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