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The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines., (2010 Elsevier Ltd. All rights reserved.)

SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound., (2010 Elsevier Ltd. All rights reserved.)

Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan (1)]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60 mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4 determined by in vitro competition kinetics (dissociation half-life t(1/2) approximately 30 min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix.