Unexpected enhancement of thrombin inhibitor potency with o -aminoalkylbenzylamides in the P1 position

Rittle, Kenneth E.; Barrow, James C.; Cutrona, Kellie J.; Glass, Kristen L.; Krueger, Julie A.; Kuo, Lawrence C.; Lewis, Sidney D.; Lucas, Bobby J.; McMasters, Daniel R.; Morrissette, Matthew M.; Nantermet, Philippe G.; Newton, Christina L.; Sanders, William M.; Yan, Yong-Bin; Vacca, Joseph P.; Selnick, Harold G.

doi:10.1016/s0960-894x(03)00732-7

Cited by 27 publications

(29 citation statements)

References 19 publications

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“…Some trypsin-like serine proteases accept chloro-substituted benzylamides as the P1 anchor [45]. For instance, an excellent potency was found for substrate analogue inhibitors of thrombin [46] and Factor Xa [47] containing a 2-(aminomethyl)-5chlorobenzylamide. However, the previously published inhibitors 71-75 (Table 8) [26,39] have reduced affinity compared with their 4-amidinobenzylamide analogues shown in Table 4.…”

Section: Substrate Analogue Inhibitorsmentioning

confidence: 99%

Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation

Meyer

Sielaff

Hammami

et al. 2013

Biochemical Journal

122

132

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TMPRSS2 (transmembrane serine proteinase 2) is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein HA (haemagglutinin) of influenza viruses with a monobasic cleavage site, which is a prerequisite for virus fusion and propagation. Furthermore, it activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS-CoV (severe acute respiratory syndrome coronavirus). Increased TMPRSS2 expression was also described in several tumour entities. Therefore TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in Escherichia coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases. Two inhibitor types were identified which inhibit TMPRSS2 in the nanomolar range. The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety at the P1 position, whereby some of these analogues possess inhibition constants of approximately 20 nM. An improved potency was found for a second type derived from sulfonylated 3-amindinophenylalanylamide derivatives. The most potent derivative of this series inhibits TMPRSS2 with a K(i) value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. On the basis of the inhibitor studies, a series of new fluorogenic substrates containing a D-arginine residue at the P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.

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Section: Substrate Analogue Inhibitorsmentioning

confidence: 99%

Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation

Meyer

Sielaff

Hammami

et al. 2013

Biochemical Journal

122

132

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“…In agreement with these findings, similar compounds bearing the 2-aminomethyl-5-chlorobenzylamine moiety showed lower affinities for trypsin (with Ser 190) than thrombin (with Ala 190). [23] In MT2 L785D variants, the inhibitory effects of compounds 3 and 4 decreased six-to 50-fold compared with those observed with wild-type MT2 (Table 1). In the wild-type enzyme, a favorable hydrophobic interaction between the cyclohexane ring and Leu 785 might account for the improved binding affinity, at least in the case of 3.…”

Section: A757smentioning

confidence: 88%

Insights into Matriptase‐2 Substrate Binding and Inhibition Mechanisms by Analyzing Active‐Site‐Mutated Variants

et al. 2011

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“…Using the same strategy, thrombin inhibitors 67a-d, incorporating o-aminoalkylbenzylamides in the P1 position, were derived from 66 (Scheme 13) and found to enhance potency and selectivity [65] ( Table 6). …”

Section: Thrombin Inhibitorsmentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

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Unexpected enhancement of thrombin inhibitor potency with o -aminoalkylbenzylamides in the P1 position

Cited by 27 publications

References 19 publications

Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation

Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation

Insights into Matriptase‐2 Substrate Binding and Inhibition Mechanisms by Analyzing Active‐Site‐Mutated Variants

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

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