Screening Library of Serine Hydrolase Inhibitors

Introduction

The advertised selection of serine hydrolase inhibitors, developed by the Boger group, represents a small, but powerful library of urea-derived molecules that can bind irreversibly to the target enzyme by active site carbamoylation of the catalytic serine.1 There are approximately 240 different human serine hydrolases, of which only half have been characterized to date and a majority still lack selective inhibitors to aid in the identification of the enzyme’s role or targeted substrates.2-3 It has been shown that the reactivity and selectivity of the inhibitors can be tuned by changing substituents in the leaving group (head group, aniline or pyrazole), by the use of different linker domains (cyclic and acyclic diamines or piperidine), or by attaching different groups to the Boc-protected nitrogen of the linker (Figure 2 and 3).1

Advantages

  • Library of irreversible serine hydrolase inhibitors may serve as initial leads for in vivo pharmaceutical probes to define the function of an uncharacterized serine hydrolase.
  • The compounds can be used as building blocks to create novel inhibitors for this class of enzymes.
  • Boc-protected amines can be derivatized to install a side chain with active site recognition features, while simultaneously improving potency and selectivity for targeted serine hydrolase.

Representative Schemes and Applications

Figure 2 shows a small SAR study of 44 compounds (3 head groups x 3 linker domains  and multiple diversification groups). These were tested on eight serine hydrolases for the three different head groups, 2-aminopyridine (2-AP), 4-trifluoromethylaniline (4-TFMA), and 2-fluoroaniline (2-FA) as well as the three different central linker diamines, the six-membered cyclic diamine (6-CDA), the seven-membered cyclic diamine (7-CDA), and the acyclic diamine (ACDA).1 The % inhibition of the various derivatives (tested at 5 µM) of each category (head group, central linker) have been added up to show a trend.

Head Group Comparison

Central Linker Diamine Comparison

Figure 2 Comparison of the summed up % inhibition of the three head groups and the three central linkers on eight serine hydrolases.

The serine hydrolase ABHD6-2 shows a clear trend for both the head group aniline and the linker domain. According to this trend the serine hydrolase inhibitor 7 (SHI-7) has the best head group and linker domain combination for developing inhibitors of the enzyme ABHD6-2 (Figure 3).

Figure 3 Observed trends for ABHD6-2 inhibition with different head groups (top) and linker domains (bottom).

 

Special thanks to Manuela Brutsch, Aleksandar Radakovic, and Dale Boger for contributing this technology spotlight.

 

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