CGP-55128A

A new concept used to design a novel, completely non-peptide class of potent, orally active human renin inhibitors of low mol. weight is described.The rationale was based on modeling studies and on the subsequent discovery of the non-substrate binding pocket S^sp₃ by X-ray crystallog. of enzyme-inhibitor complexes.The truncated dipeptide transition state mimetics with an extended hydrophobic (P₃-P₁)-moiety lack the P₄-P₂ spanning peptide-like backbone of all previously reported renin inhibitors.The addnl. P^sp₃ residue attached to the P₃ heterocycle provided enhanced binding affinities up to the sub-nanomolar range.In vitro SAR data for two series of compounds with structurally different P₃-P₁ side chains as well as the pronounced blood pressure lowering effects of 2 inhibitors in marmosets is described.