Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors.

We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound exhibited excellent potencies in cells and proliferation studies, good selectivity, activities, and an excellent PK profile.

Spontaneous cardiomyopathy in young Sprague-Dawley rats: evaluation of biological and environmental variability.

Cardiovascular safety signals in nonclinical studies remain among the main reasons for drug attrition during pharmaceutical research and development. Drug-induced changes can be functional and/or associated with morphological alterations in the normal heart histology. It is therefore crucial to understand the normal variations in histology to discriminate test article-related changes from background lesions.