Fused bicycles as arylketone bioisosteres leading to potent, orally active thiadiazole H3 antagonists.

A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.

Discovery of a potent thiadiazole class of histamine h3 receptor antagonist for the treatment of diabetes.

A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days.

Synthesis and structure-activity relationship (SAR) study of 4-azabenzoxazole analogues as H3 antagonists.

The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.

Discovery of a series of potent arylthiadiazole H(3) antagonists.

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.

The synthesis and structure-activity relationship of 4-benzimidazolyl-piperidinylcarbonyl-piperidine analogs as histamine H3 antagonists.

A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) View Article and Find Full Text PDF

Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists.

Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.

Synthesis and structure-activity relationships of 2-(1,4'-bipiperidin-1'-yl)thiazolopyridine as H3 receptor antagonists.

A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.

Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

In the late 1980's 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.

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.

Reduction of CYP450 inhibition in the 4-[(1H-imidazol-4-yl)methyl]piperidine series of histamine H3 receptor antagonists.

A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.

Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold.

We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g.

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.

Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687).

We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively.

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) 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.

Identification of a novel, orally bioavailable histamine H(3) 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.