Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state.

Abstract

The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1', P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50 = 6.0 x 10(-9) M) and pepsin (IC50 = 3.5 x 10(-7) M) to the same extent as renin (IC50 = 8.5 x 10(-10) M), and thus was not specific for renin. The reduction of the beta-carbonyl group to methylene group in beta-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i: IC50 = 1.1 x 10(-7) M vs. 1: IC50 = 2.4 x 10(-9) M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

“…In contrast, P1 mutations remain largely unexplored and have been studied only in special cases. [10][11][12][13] As a result, elaborate and exhaustive P1 site mutations have not yet been performed to investigate their influence on the affinity or specificity of protease inhibitors. Therefore, we considered the development of novel synthetic strategies leading to efficient P1 mutations as highly attractive goal.…”

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

“…No hydrogen bond is formed between the enzyme active site and the hydrogen atom that is a constituent of the NH group belonging to the amino acid at the P 2 position of the P 3 -P 2 peptide bond. Therefore, the hydrogen atom could be substituted for a short alkyl, for example, the methyl group [36][37][38][39]. Introduction of an N-methyl amino acid, such as MeLeu, MeVal, or MeHis, increases resistance of the P 3 -P 2 bond to proteolytic enzymes, while their affinity to renin remains unaffected [40,41].…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…The method was based on a cyanide addition to leucinal, easily prepared from (2S,3S)-isoleucine, and then separation of the diastereomeric product mixture [75]. Recently, Li et al have synthesized isonorstatine starting from L-tartaric acid, which was converted to a threose imine and then introduced to a highly stereoselective addition of 1-butene-3-yl [76].…”