Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

Abstract

By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

“…The comparative analysis of the platelet aggregation inhibition results of this series of 2-oxopiperazine derivatives of general formula B with those of our previously reported series of urea analogues A [47], shows that the conformational restriction of the 2-oxopiperazine ring does not affect the binding of the compounds to PAR1, as the best compounds of both series displayed similar activity values. …”

“…The Ni Raney catalyzed hydrogenation of these -amino nitriles led to the respective 2-oxopiperazine derivatives (R)-and (S)-34a and -35a, but in yields lower than 40%, due to retro-Strecker and cyano removal side reactions. After studying other catalysts 11 and hydrogenation conditions, it was deduced that the best reduction conditions were hydrogen transfer from hydrazine monohydrate using Ni Raney as catalyst under refluxing MeOH for 10 min [47]. In this way, the epimeric mixtures 34a and 35a were obtained in 55-86% yield and were chromatographically resolved into the (R)-and (S)-epimers.…”

“…Some of these derivatives showed moderate antiaggregant activity in a screen of inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN [47]. We now describe the synthesis and biological evaluation of a library of pseudodipeptidebased 2-oxopiperazine derivatives of general formula B, which could be considered as conformational restricted analogues of the urea derivatives A.…”

Chameleonic reactivity of α-amino nitrile-derived ureas. Synthesis of highly functionalized imidazolidin-2-one and imidazolidine-2,4-dione derivatives

“…These hydantoins derivatives were isolated from the reaction mixtures as TFA salts in higher than 95 % yield and were screened as antagonists of the thrombin receptor PAR1 in an assay of human platelet aggregation inhibition. 14 None of them displayed significant activity at 0.1 mg/mL concentration. b Isolated yield.…”

“…10 On the other hand, -amino nitrile-derived ureas are intermediates in the synthesis of diverse pharmacologically active hydantoin derivatives from -amino nitriles. [11][12][13] In view of these precedents and in the context of a medicinal chemistry project focused on the search of antagonists of the thrombin receptor PAR1, 14,15 by exploring the use of -amino acid-derived amino nitriles as molecular diversity generators, 16 we have recently described a versatile solvent-free synthesis of basic amino acid-derived N-(cyanomethyl)ureas of general formula A. 17 Now, taking into account that hydantoins (imidazolidine-2,4-diones) are included among privileged scaffolds in medicinal chemistry, 18,19 natural products [20][21][22][23][24][25][26] and organic synthesis, 19,27 we have studied and report herein the cyclization of cyanomethylureas A to imidazolidin-2-one derivatives B (Scheme 1).…”