Amino acid derived quinazolines as Rock/PKA inhibitors.
SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N
kinases PKA Rock Rock PKA Rock cytochrome P-450 Rock PKA amino acid quinazolinones amino acid quinazolinones amino acid quinazolines Amino acid quinazolines Rock (I & II)