title: Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438).
abstract: Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.
authors.affiliation: Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, 11301 Wilshire Blvd., Bldg. 113, CA 90073, USA. jaishin@ucla.edu
authors.forename: Jai Moo
authors.initials: JM
authors.lastname: Shin
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.forename: Keith
authors.initials: K
authors.lastname: Munson
authors.forename: David
authors.initials: D
authors.lastname: Strugatsky
authors.forename: Elmira
authors.initials: E
authors.lastname: Tokhtaeva
authors.forename: Olga
authors.initials: O
authors.lastname: Vagin
authors.forename: George
authors.initials: G
authors.lastname: Sachs
mesh_terms: D000165:Acridine Orange / Q000378:metabolism; D000818:Animals; D005456:Fluorescent Dyes / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054328:Proton Pump Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012984:Software; D013237:Stereoisomerism; D013270:Stomach / Q000187:drug effects* / Q000201:enzymology; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D005456:Fluorescent Dyes; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D017506:H(+)-K(+)-Exchanging ATPase; D000165:Acridine Orange