Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo

We found that pyridoxal phosphate shows considerable inhibition of cathepsi ns. CLIK-071, in which the phosphate ester of position 3 of pyridoxal phosp hate was replaced by propionate, strongly inhibited cathepsin B. Three new types of synthetic pyridoxal propionate derivatives showing specific inhibi tion of cathepsin K were developed. New synthetic pyridoxal propionate deri vatives, -162, -163, and -164, in which the methyl arm of position 6 of CLI K-071 was additionally modified, strongly inhibited cathepsin K and catheps in S weakly, but other cathepsins were not inhibited. CLIK-166, in which th e position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and positi on 5 is additionally modified, showed cathepsin K-specific inhibition at 10 (-5) M. Pit formation due to bone collagen degradation by cathepsin K of ra t osteoclasts was specifically suppressed by administration of CLIK-164, bu t not by inhibitors of cathepsin L or B. (C) 2000 Academic Press.