title: Pyrrolo[2,3-d]pyrimidines as inhibitors of cAMP-phosphodiesterase. Structure-activity relationship.
abstract: The effects of pyrrolo[2,3-d]pyrimidine compounds (7-desazapurines) on cAMP hydrolyzing, calmodulin dependent and calmodulin independent phosphodiesterase were studied. Phosphodiesterase inhibition depended on the chemical nature of substituents attached to the pyrrolo-pyrimidine-nucleus at positions 2, 4, 5, 6 and 7. Among a total of 28 compounds tested, the 4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dicarbaldehyde (9) was the most potent inhibitor of phosphodiesterase activity (IC50 = 16 microM). In addition to the 5,6-disubstitution, position 2 of the pyrrolo-pyrimidine derivatives had to be unsubstituted and position 4 had to bear an amino-group for an optimal inhibitory effect. Calmodulin dependent and calmodulin independent isozymes were affected to the same extent. Inhibition of PDE activity was reversible upon removal of the pyrrolo-pyrimidine derivative 9 and non-competitive with respect to cAMP (Ki = 27 microM).
authors.affiliation: Pharmazeutisches Institut der Universität, Pharmazeutische Chemie, Tübingen, Federal Republic of Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klumpp
authors.forename: M
authors.initials: M
authors.lastname: Frey
authors.forename: G
authors.initials: G
authors.lastname: Kleefeld
authors.forename: A
authors.initials: A
authors.lastname: Sauer
authors.forename: K
authors.initials: K
authors.lastname: Eger
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D002147:Calmodulin / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D006868:Hydrolysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002147:Calmodulin; D007527:Isoenzymes; D011743:Pyrimidines; D011758:Pyrroles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1