PDBsum entry 2chm

Hydrolase

PDB id: 2chm

Contents

Protein chain

323 a.a. *

Ligands

3P4

MES

Metals

_ZN

_MG

Waters ×515

* Residue conservation analysis

PDB id:

2chm

Name:

Hydrolase

Title:

Crystal structure of n2 substituted pyrazolo pyrimidinones - a flipped binding mode in pde5

Structure:

Cgmp-specific 3', 5'-cyclic phosphodiesterase, camp- specific 3', 5'-cyclic phosphodiesterase 4b. Chain: a. Fragment: catalytic domain residues (residues 534-858 with subdomain replaced with pde4 subdomain). Synonym: 3', 5' cgmp-cyclic phophodiesterase 5a catalytic domain chimera, cgb-pde, cgmp-binding cgmp-specific phosphodiesterase, dpde4, pde32. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five.

Resolution:

1.60Å R-factor: 0.195 R-free: 0.223

Authors:

C.M.N.Allerton,C.G.Barber,K.C.Beaumont,D.G.Brown,S.M.Cole,D.Ellis, C.A.L.Lane,G.N.Maw,N.M.Mount,D.J.Rawson,C.M.Robinson,S.D.A.Street, N.W.Summerhill

Key ref:

C.M.Allerton et al. (2006). A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability. J Med Chem, 49, 3581-3594. PubMed id: 16759100 DOI: 10.1021/jm060113e

Date:

15-Mar-06 Release date: 08-Jun-06

Protein chain

O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 875 a.a.

Struc: 323 a.a.*

Protein chain

Q07343  (PDE4B_HUMAN) -  3',5'-cyclic-AMP phosphodiesterase 4B from Homo sapiens

Seq: 736 a.a.

Struc: 323 a.a.*

* PDB and UniProt seqs differ at 238 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺
• Enzyme class 3: E.C.3.1.4.53 - 3',5'-cyclic-AMP phosphodiesterase.
• Reaction: 3',5'-cyclic AMP + H2O = AMP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm060113e

J Med Chem 49:3581-3594 (2006)

PubMed id: 16759100

A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.

C.M.Allerton, C.G.Barber, K.C.Beaumont, D.G.Brown, S.M.Cole, D.Ellis, C.A.Lane, G.N.Maw, N.M.Mount, D.J.Rawson, C.M.Robinson, S.D.Street, N.W.Summerhill.

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.