Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Abstract

Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

Potent and Selective Double-Headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma

“…8,9 Therefore, to precisely control biological processes and improve the safety profile, selective inhibition of nNOS over the other two isoforms is important for any potential therapeutic agent. The close similarity of active site structures in all three isoforms 10,11 presents a critical barrier to the design of selective nNOS inhibitors.…”

Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations

“…11,12 However, the therapeutic control of NO synthesis is difficult because of the challenge to achieve highly selective inhibition of the specific isoforms. 13 Each one of the three isozymes is associated with different functions: nNOS is devoted to neuronal signaling, iNOS to the immune response, and eNOS to smooth muscle relaxation and blood pressure regulation. 14 Therefore, selective inhibition of nNOS over the other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects related to iNOS and eNOS inhibition.…”

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

“…[36] 1996 veröffentlichte Zeneca FXa-Inhibitoren wie 24 (Schema 10) mit einer nur noch schwach basischen Gruppe. [37] Lange Zeit wurde hier irrtümlicherweise die Pyridylpiperidinylgruppe für die basische P1-Gruppe gehalten.…”

“…[37] Lange Zeit wurde hier irrtümlicherweise die Pyridylpiperidinylgruppe für die basische P1-Gruppe gehalten. [36] Aus einer Röntgen-strukturanalyse mit Trypsin wurde jedoch ersichtlich, dass sich die Chlornaphthylgruppe in der S1-Tasche befindet. Es lag nahe, dass eine vergleichbare Orientierung auch für FXa zutrifft.…”