SELECTIVE-INHIBITION OF CYCLIC-AMP-DEPENDENT PROTEIN-KINASE BY ISOQUINOLINE DERIVATIVES

A large series of isoquinoline derivatives was synthesised including d erivatives of isoquinoline, isoquinolino[3,4-c]furazan, 1,2-dihydro-1- oxoisoquinoline, 6-oxopyrimido[1 ,2-b]isoquinoline, benzo[c][1,8]-naph thyridine, pyrazino[2,3-c]isoquinoline and benzimidazoe[2,1 -a]isoquin oline as well as further structurally related isoquinoline derivatives and pyrido-2,3-furazans. Representatives of all of these classes of i soquinolines are potent and selective inhibitors of the cyclic AMP-dep endent protein kinase (PKA) catalytic subunit (cAK) from rat liver, Th e most effective cAK inhibitors are a series of 1,3-di-substituted and 1,3,4-tri-substituted isoquinolines (IC50 values 30 - 50 nM) (compoun ds A1, A2, A3, A4 and A5) and 2-ethylcarboxy-3-amino-5,6-dihydro-6-oxo benzo[c] [1 8]naphthyridine (El) (IC50 0.08 mu M) Compounds A1-A5 inhi bit cAK in a fashion that is competitive with respect to ATP as substr ate, The isoquinoline inhibitors A1-A5 are ineffective or very poor in hibitors of wheat embryo Ca2+-dependent protein kinase (CDPK) and rat brain Ca2+-dependent protein kinase C (PKC), chicken gizzard myosin li ght chain kinase (MLCK) and potato tuber cyclic nucleotide-binding pho sphatase (Pase), E1 is a moderately effective inhibitor of CDPK and PK C (IC50 values 30 and 61 mu M, respectively), The bisisoquinoline-1 (2 H)-one compound B7 inhibits cAK, CDPK, PKC and MLCK (IC50 values 8, 95 , 24 and 7 mu M, respectively) as does J1 -bromophenyl)pyrrolo[2,3-c]i soquinoline-5(4H)-one] (IC50 values 2, 50, 44 and 7 mu M, respectively ), The very potent isoquinoline-derived cAK inhibitors found here invo lve substitution of the N-containing isoquinoline ring system and thes e inhibitors show high specificity for cAK.