First generation PDE3 inhibitors Recognition that the knowledge about PDE could be used to develop drugs that were PDE inhibitors led to extensive research. Most studies used analogues of the nucleotide substrates or derivatives of natural product inhibitors such as
xanthine (e.g.
theophylline) and
papaverine. The
active site of PDE3 can be considered as a summary of ideas about receptor topography resulting from the first generation inhibitors. The model of the Wells
et al. version as cited in Erhardt and Chou (1991) includes the following: • A
phosphate binding area • A
lipophilic area that accommodates the
non-polar side of the
ribose moiety • A
pyrimidine binding site • An
imidazole binding site portion of the
pyrimidine binding site • A sterically hindered site • An area with bulk tolerance
Second generation PDE3 inhibitors Since selective PDE3 inhibitors were recognised to be
cardiotonic drugs there has been great interest in developing new drugs in this category. A large number of heterocyclic compounds have been synthesized during related research. These compounds constitute a second generation of PDE inhibitors. Although they have been directed mostly at PDE3, they present significant
structure-activity relationship for the PDEs in general. ) – P (
phenyl) – I (
imidazole) pattern of CI-930 A "heterocycle-phenyl-imidazole" (H-P-I) pattern has been considered to be necessary for positive
inotropic activity in cardiac muscle and many second generation inhibitors fit this pattern.
The heterocycle region: Within each
heterocycle there is the presence of a dipole and an adjacent acid proton (an amide function). These atoms are believed to mimic the
electrophilic center in the phosphate group in cAMP and are confirmed as the primary site of binding. The heterocycle is a
transition state analogue inhibitor of PDE.
Alkyl groups, limited to either
methyl or
ethyl, on the heterocyclic ring usually enhance potency, with occasional exceptions.
The phenyl region: It seems that an electron rich centre, such as
phenyl, needs to be present. The beneficial effects of small
alkyl groups on the heterocycle could be to twist the central ring away from exact coplanarity with the heterocyclic ring. There is a similar twist in
cAMP and there is general agreement that high affinity PDE3 inhibitors should adopt an energetically favoured planar conformation that mimics the anti conformation of cAMP.
The imidazole region: Various substituents have been placed at the para-position of the central phenyl ring. They are electron rich moieties and apparently a positively charged moiety cannot be tolerated in this region of the PDE receptor. There is general agreement about this inhibitor potency:
lactam ≥ alkyl-CONH- ≥
imidazoyl =
pyridine in place of the central phenyl with its
nitrogen in the analogous 4 position ≥ alkyl-S- > simple
ether >
halide =
amine >
imidazolium (which is totally inactive). Identification of features common to the most selective inhibitors has led to a "five-point model" with: • Presence of a strong dipole (
carbonyl moiety) at one end of the molecule. • An adjacent acid proton. • A small sized alkyl substituent on the heterocyclic ring. • A relatively flat overall topography. • An electron rich centre and/or a hydrogen bond acceptor site opposite to the dipole. == Examples of selective PDE3 inhibitors ==