Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors

Y Xia; S Chackalamannil; M Czarniecki; H Tsai; H Vaccaro; R Cleven; J Cook; A Fawzi; R Watkins; H Zhang

doi:10.1021/jm970495b

Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors

J Med Chem. 1997 Dec 19;40(26):4372-7. doi: 10.1021/jm970495b.

Authors

Y Xia¹, S Chackalamannil, M Czarniecki, H Tsai, H Vaccaro, R Cleven, J Cook, A Fawzi, R Watkins, H Zhang

Affiliation

¹ Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.

PMID: 9435906
DOI: 10.1021/jm970495b

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.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
Administration, Oral
Animals
Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects
Cyclic AMP / metabolism
Cyclic GMP / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 1
Cyclic Nucleotide Phosphodiesterases, Type 5
Magnetic Resonance Spectroscopy
Molecular Structure
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology
Phosphodiesterase Inhibitors / therapeutic use
Phosphoric Diester Hydrolases*
Polycyclic Compounds / chemical synthesis*
Polycyclic Compounds / chemistry
Polycyclic Compounds / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Rats
Structure-Activity Relationship

Substances

Antihypertensive Agents
Phosphodiesterase Inhibitors
Polycyclic Compounds
Pyrimidines
Cyclic AMP
Phosphoric Diester Hydrolases
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 1
3',5'-Cyclic-GMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 5
Pde5a protein, rat
Cyclic GMP