2CHM

Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5

Summary for 2CHM

• Entry DOI: 10.2210/pdb2chm/pdb
• Related: 1F0J 1JP1 1JP2 1RKP 1RO6 1RO9 1ROR 1T9R 1T9S 1TB5 1TBF 1UDT 1UDU 1UHO 1XLX 1XLZ 1XM4 1XM6 1XMU 1XMY 1XN0 1XOS 1XOT 1XOZ 1XP0 1Y2H 1Y2J
• Descriptor: CGMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE, CAMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE 4B, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase 5, inhibitor, chimera, allosteric enzyme, alternative splicing, cgmp, cgmp-binding, hydrolase, magnesium, metal-binding, nucleotide-binding, phosphorylation, zinc, camp
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 38332.68

Authors

Allerton, C.M.N.,Barber, C.G.,Beaumont, K.C.,Brown, D.G.,Cole, S.M.,Ellis, D.,Lane, C.A.L.,Maw, G.N.,Mount, N.M.,Rawson, D.J.,Robinson, C.M.,Street, S.D.A.,Summerhill, N.W. (deposition date: 2006-03-15, release date: 2006-06-08, Last modification date: 2024-05-01)

Primary citation

Allerton, C.M.N.,Barber, C.G.,Beaumont, K.C.,Brown, D.G.,Cole, S.M.,Ellis, D.,Lane, C.A.L.,Maw, G.N.,Mount, N.M.,Rawson, D.J.,Robinson, C.M.,Street, S.D.A.,Summerhill, N.W.
A Novel Series of Potent and Selective Pde5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability
J.Med.Chem., 49:3581-, 2006

PubMed Abstract: Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

PubMed: 16759100
DOI: 10.1021/JM060113E

Experimental method

X-RAY DIFFRACTION (1.6 Å)