Shirley M. Williams

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

Effect of anti-inflammatory drugs on lysosomes and lysosomal enzymes from rat liver

Abstract Steroidal and nonsteroidal anti-inflammatory drugs were tested for their capacity to stabilize, in vitro , lysosomes and inhibit lysosomal enzymes. Lysosome membrane stability was measured by determining the effects of drugs on the release of aryl sulfatase and β-glucuronidase from lysosomes which were suspended in a hypo-osmotic sucrose buffer. Lysosomes obtained from a heavy mitochondrial (3500 g ) rat liver fraction were found to be highly sensitive to membrane stabilization by naproxen, alclofenac, chloroquine, mefenamic acid, phenylbutazone, hydrocortisone, dexamethasone and methylprednisolone. Ibuprofen and flufenamic acid demonstrated moderate stabilizing activity, while indo-methacin, aspirin and clonixin showed only weak activity. Imuran, as well as other anti-inflammatory drugs, was inactive. In addition to their membrane-stabilizing activity, chloroquine was found to be a potent inhibitor of aryl sulfatase and phenylbutazone an inhibitor of β-glucuronidase activity. Hydrocortisone, dexamethasone and paramethasone inhibited aryl sulfatase activity, while no steroid tested was effective as an inhibitor of β-glucuronidase. The data in this report support the hypothesis that anti-inflammatory drugs inhibit the release of enzymes from lysosomes. In addition, several of these drugs may act as inhibitors of lysosomal enzyme activity.

Identification of a novel, orally bioavailable histamine H3 receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template

A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.

Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine.

Combining the first generation H(1) antihistamine chlorpheniramine (1) with H(3) ligands of the alkylamine type has led to the identification of compound 9d, a dual ligand of both the H(1) and H(3) receptors.

Benzimidazole-substituted (3-phenoxypropyl)amines as histamine H3 receptor ligands.

A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.

Structural determinants for histamine H1 affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs

In the late 1980s reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.

Tomoxiprole Selectively Inhibits Cyclooxygenase-2

Tomoxiprole is a nonsteroidal anti-inflammatory compound that was reported to have low ulcerogenic potential, a quality that would be expected of a cyclooxygenase-2-selective inhibitor, and, in fact, we find it is selective for this isozyme. In stably transfected COS cells, the compound inhibits recombinant human cyclooxygenase-2 (IC50 = 7 nM) more potently than recombinant cyclooxygenase-1 (IC50 = 240 nM), and similar results are obtained with partially pure ovine enzyme preparations. The compound is thus a very potent as well as selective inhibitor of cyclooxygenase-2. As is true of some other cyclooxygenase-2-selective inhibitors, tomoxiprole inhibition of cyclooxygenase-2 but not cyclooxygenase-1 is time-dependent.