Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test.

We tested the hypothesis that the stable isotope [(13)C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the (13)CO(2) produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19(*)2, CYP2C19(*)3, and CYP2C19(*)17 alleles were administered a single oral dose of [(13)C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled (13)CO(2) and (12)CO(2) were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of (13)CO(2)/(12)CO(2) after [(13)C]pantoprazole relative to (13)CO(2)/(12)CO(2) at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB(15) to DOB(120), and area under the DOB versus time curve (AUC(0-120) and AUC(0-infinity)) were significantly different among three genotype groups (CYP2C19(*)1/(*)1, n = 10; CYP2C19(*)1/(*)2 or CYP2C19(*)1/(*)3, n = 10; and CYP2C19(*)2/(*)2, n = 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p < 0.01); linear regression analysis indicated a gene-dose effect relationship (r(2) ranged between 0.236 and 0.522; all p < 0.05). These breath test indices were significantly lower in PMs than IMs (p < 0.05) or EMs (p < 0.01) of CYP2C19. [(13)C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r = -0.74; p = 0.038). These feasibility data suggest that the [(13)C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.

Pharmacophore modeling and three dimensional database searching for drug design using catalyst: recent advances.

Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore. As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. This paper is an update to the original paper published in this journal earlier: Kurogi, Y, and Guner, O. F. "Pharmacophore Modeling and Three-Dimensional Database Searching for Drug Design Using Catalyst," in Current Medicinal Chemistry, 2001, 8(9), 1035-1055.

1,2,4-Triazolo[5,1-i]purine derivatives as highly potent and selective human adenosine A(3) receptor ligands.

A series of triazolopurines showed structural similarity to human adenosine A(3) receptor antagonist, 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]triazolo[1,5-c]quinazoline (MRS 1220, 1). In this study, we found novel 1,2,4-triazolo[5,1-i]purine derivatives (2) showing human adenosine A(3) receptor affinities. The compounds were obtained in two steps from 5-amino-4-cyanoimidazole (33). The affinity was determined in radioligand binding assays for the cloned human adenosine A(1), A(2A), A(2B), and A(3) receptors. After the structure-activity relationship was analyzed, we determined that there was a mild parabolic relationship between the length of alkyl groups at the 5-position and the affinities at the A(3) receptor and positive correlation between the length of the substituents on phenyl groups at the 8-position and the affinities at the A(2A) receptor. These investigations led to potent and selective human adenosine A(3) receptor ligands. The most potent A(3) receptor ligand (5-n-butyl-8-(4-methoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (27, K(i) = 0.18 nM) and the most selective A(3) receptor ligand against A(1), A(2A), and A(2B) receptors, (5-n-butyl-8-(4-n-propoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (29, >19 600), were discovered.

Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease.

Mesangial cells (MC) serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of glomerular hemodynamics, and a phagocytic function allowing removal of macromolecules and immune complexes. The proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental animal models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix in the mesangium and glomerulosclerosis. Reduction of MC proliferation in glomerular disease models by treatment with heparin, low-protein diet, or antibodies to platelet-derived growth factor (PDGF), have been shown to reduce extracellular matrix expansion and glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer therapeutic opportunities for the treatment of proliferative glomerular disease. It is also known that the MC proliferation is inhibited by many kinds of pharmacological drugs, for example, angiotensin converting enzyme (ACE) inhibitors, leukotriene D(4) (LTD(4)) antagonists, PDGF inhibitors, matrix metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG-CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This review summarizes the recently reported MC proliferation inhibitors with their pharmacological properties on the basis of their chemical structures.

Facile synthesis of fused 1,2,4-triazolo[1,5-c]pyrimidine derivatives as human adenosine A3 receptor ligands.

A facile synthetic method for fused triazolopyrimidine derivatives having high affinity and selectivity for human adenosine A(3) receptors is reported. The fused triazolopyrimidine derivatives were easily prepared by one-pot reaction using acylhydrazines and imidates prepared from amine derivatives bearing cyano group and orthoesters in situ. This synthetic method was useful in finding new tricyclic adenosine A(3) receptor antagonists and also in diversifying the substituents at two positions on the fused triazolopyrimidine ring.

Structure-activity relationships of adenosine A3 receptor ligands: new potential therapy for the treatment of glaucoma.

Structure-activity relationships (SAR) of fused 1,2,4-triazolo[1,5-c ]pyrimidine were performed. Various substituents were introduced into the heterocyclic ring to improve the potency of adenosine A(3) receptor binding affinity and A(3)-selectivity against other subtypes. Potent and selective A(3) receptor antagonists were identified and were evaluated in a monkey model of intraocular pressure by eye-drop administration. As a result, compound 1c (OT-7999) was found to significantly decrease intraocular pressure in the animal model.