title: Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors.
abstract: Polycyclic pyrazolo[3,4-d]pyrimidines (represented by 3 and 4) were synthesized as analogues of the recently reported polycyclic guanine phosphodiesterase (PDE) inhibitors. From the structure-activity relationship (SAR) development of a series of compounds, it was discovered that C-3 benzyl and N-2 methyl disubstitution on the pyrazole ring gave the best combination of potency and selectivity for PDE1 and PDE5 cGMP PDEs as represented by compound 4c: PDE1, IC50 = 60 nM; PDE3, IC50 = 55,000 nM; PDE5, IC50 = 75 nM. These compounds were also evaluated in vivo and found to be good orally active antihypertensives in laboratory animal models. Finally, comparisons were made of the in vitro and in vivo profiles of the pyrazolo-[3,4-d]pyrimidine compound 4c with those of two representative guanine compounds.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xia
authors.forename: S
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: M
authors.initials: M
authors.lastname: Czarniecki
authors.forename: H
authors.initials: H
authors.lastname: Tsai
authors.forename: H
authors.initials: H
authors.lastname: Vaccaro
authors.forename: R
authors.initials: R
authors.lastname: Cleven
authors.forename: J
authors.initials: J
authors.lastname: Cook
authors.forename: A
authors.initials: A
authors.lastname: Fawzi
authors.forename: R
authors.initials: R
authors.lastname: Watkins
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D011083:Polycyclic Compounds; D011743:Pyrimidines; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP