Design of novel inhibitors of aminopeptidases. Synthesis of peptide-derived diamino thiols and sulfur replacement analogs of bestatin

• Published in: Journal of medicinal chemistry 1988-11, Vol.31 (11), p.2199-2211
• Main Authors: Gordon, E. M, Godfrey, J. D, Delaney, N. G, Asaad, M. M, Von Langen, D, Cushman, D. W
• Format: Article
• Language: English
• Subjects: Aminopeptidases - antagonists & inhibitors; Animals; bestatin; Binding Sites; Brain - enzymology; Chemistry; Diamines - chemical synthesis; Diamines - pharmacology; Exact sciences and technology; Hydrolysis; Leucine - analogs & derivatives; Organic chemistry; Peptides; Peptides - chemical synthesis; Peptides - pharmacology; Preparations and properties; Rats; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00119a023

Investigations were directed toward inhibition of an aminopeptidase, isolated from rat brain, which has been implicated in the metabolic inactivation of enkephalins. The design rationale and synthesis of novel peptidyl diamino thiol inhibitors of rat brain aminopeptidase are presented, along with accompanying structure-activity analysis. Some of the reported compounds are highly active aminopeptidase inhibitors and possess enzyme inhibitory potency in the nanomolar range (62; I50 = 1 nM). Analysis of the data permits speculations on possible modes of binding of diamino thiols to aminopeptidase. Other investigations were directed toward understanding the mode of enzyme binding of the naturally occurring aminopeptidase inhibitor bestatin. On the basis of published models of enzyme binding, replacement of the C-2 hydroxyl group of bestatin by a sulfhydryl group was anticipated to lead to enhanced inhibition due to a strengthened interaction of this group with enzymic zinc. Contrary to expectations, "thiobestatin" inhibited rat brain aminopeptidase with only the same degree of effectiveness as the corresponding alcohol. Speculations on the possible mode of enzyme-inhibitor binding of bestatin are offered.