Chemical properties PDE3 inhibitor

h (heterocycle) – p (phenyl) – (imidazole) pattern of ci-930

a “heterocycle-phenyl-imidazole” (h-p-i) pattern has been considered necessary positive inotropic activity in cardiac muscle , many second generation inhibitors fit pattern.

the heterocycle region: within each heterocycle there presence of dipole , adjacent acid proton (an amide function). these atoms believed mimic electrophilic center in phosphate group in camp , confirmed primary site of binding. heterocycle transition state analogue inhibitor of pde. alkyl groups, limited either methyl or ethyl, on heterocyclic ring enhance potency, occasional exceptions.

the phenyl region: seems electron rich centre, such phenyl, needs present. beneficial effects of small alkyl groups on heterocycle twist central ring away exact coplanarity heterocyclic ring. there similar twist in camp , there general agreement high affinity pde3 inhibitors should adopt energetically favoured planar conformation mimics anti conformation of camp.

the imidazole region: various substituents have been placed @ para-position of central phenyl ring. electron rich moieties , apparently positively charged moiety cannot tolerated in region of pde receptor. there general agreement inhibitor potency: lactam ≥ alkyl-conh- ≥ imidazoyl = pyridine in place of central phenyl nitrogen in analogous 4 position ≥ alkyl-s- > simple ether > halide = amine > imidazolium (which totally inactive).

identification of features common selective inhibitors has led “five-point model” with:

^ erhardt p.w.; chou y. (1991). topographical model c-amp phosphodiesterase iii active site . life sciences, 49(8): 553-568. 
^ fossa p.; boggia r.; mosti l. (1998). toward identification of cardiac cgmp inhibited-phosphodiesterase catalytic site . journal of computer-aided molecular design, 12(4): 361-372.