Synthesis and SAR of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones as Inhibitors of D-Amino Acid Oxidase

Abstract

A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of D-amino acid oxidase (DAAO). Inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC(50) values of the compounds ranging from 70 nM to greater than 100 µM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Some of these compounds were given to mice orally together with D-serine to assess their effects on plasma D-serine pharmacokinetics.

Figure 1

Representative inhibitors of DAAO.

Figure 2

(A) Compound 5 (green) bound to the active site of DAAO (3G3E). (B) Proposed binding mode of 6a (white) to the active site of DAAO. Hydrogen-bonding interactions are shown as yellow dashed lines.

Figure 3

Preliminary SAR studies of analogues of 6a.

Scheme 1. Synthesis of 1-Hydroxy-1H-benzo[d]imidazol-2(3H)-ones

Reagents and conditions: (a) BnONH₂, DCM, rt, 80–100%. (b) Et₃N, DCM, rt, 64–84%. (c) Pb(OAc)₄, CHCl₃, rt, 9–83%. (d) H₂, 10% Pd/C, EtOH, 13–90% or HBr, AcOH, reflux, 28%.

Figure 4

Effects of DAAO inhibitors on plasma d-serine levels following oral coadministration.