ABSTRACT
We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.
ABSTRACT
The angularly fused 6,3,5-tricyclic system is readily generated via a cascade cyclization under acid promotion. The reaction proceeds at room temperature with high stereochemical fidelity from the electrophilic center of the epoxide to the cyclopropane product. This methodology provides a potentially useful approach for the synthesis of mycorrhizin A and its analogues.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Biological Products/chemical synthesis , Coumarins/chemical synthesis , Anti-Bacterial Agents/chemistry , Biological Products/chemistry , Combinatorial Chemistry Techniques , Coumarins/chemistry , Cyclization , Molecular StructureABSTRACT
The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation. The absolute configurations of xestodecalactones B and C have been determined via these syntheses.
