A structural screening approach to ketoamide-based inhibitors of cathepsin K

Design of Cathepsin K Inhibitors for Osteoporosis

“…Further insights into the binding of these heterocycles and the ketoamide inhibitors in general were first obtained from the X-ray co-crystal structure of compound 169 bound to cathepsin K as shown in Figure (1D). Although, the orientation of the P 1 and P 2 groups were in line with modelling predictions, the P 1' pyrazole moiety in compound 169, besides an interaction with the indole of 184 Trp, had an additional binding contribution from 18 Gln through two water molecules. Another surprising aspect was that the hydroxyl of the hemithioketal was not oriented into the oxyanion hole of the protein.…”

“…N-methyl pyrazole 170, although not as potent due to the loss of a hydrogen bond with 184 Trp, was a very selective compound against the other cathepsins (See Table 15), while N-methyl pyrazole 171 retained its potency with no enhancement of selectivity. Encouraged by these results, a number of P 1' Nalkyl/aryl substituted pyrazoles were investigated.…”

“…Initial efforts focussed on securing an interaction with 184 Trp, which is conserved among the cysteine cathepsins. Various five and six membered heterocycles were studied.…”

“…Aaron Miller investigated a structural screening approach [184]. This exploration involved an ACD search of secondary alcohols that were filtered on the basis of size and cost, and then docked into the cathepsin K active site.…”

Novel, potent P2–P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors

“…4 This group has previously reported potent a-ketoamide inhibitors of cathepsin K. [5][6][7][8][9] The P 2 pantolactone moiety of ketoamide 1 (IC 50 = 3.0 nM) was discovered through structural screening of the available chemical directory (ACD) as part of an ongoing structure/activity relationship analysis. 10 Although quite potent, inhibitor 1 exhibited poor pharmacokinetic (PK) properties in rats with a low terminal half-life and no oral bioavailability. Poor PK parameters were presumably due, at least in part, to the observed instability of the lactone in plasma.…”