Selective Histamine H1 Receptor Antagonist Research Articles

Preliminary study of histamine H4 receptor expressed on human CD4+ T cells and its immunomodulatory potency in the IL-17 pathway of psoriasis

BackgroundPrevious studies have shown the expression of histamine H4 receptor (H4R) on CD4+ T cells, especially human CD4+ Th2-polarized T cells. ObjectiveThis study aimed to investigate the role of H4R on these effector T cells in psoriasis. MethodsWe enrolled three patients each with active psoriasis, inactive psoriasis, scalp seborrheic dermatitis, and three normal controls, and compared the basal expression of H4R mRNA in their peripheral blood CD4+ T cells. Then, we identified H4R expression in dermal CD4+ T cells. Furthermore, we investigated H4R expression after stimulating separated peripheral blood CD4+ T cells with several inflammatory cytokines. ResultsThe results showed higher H4R expression in the active psoriasis group compared to the inactive psoriasis group. It was interesting that interleukin (IL)-23, which is a representative cytokine contributing to Th17 cell differentiation, stimulated H4R expression significantly. After adding a selective H4R antagonist (JNJ-7777120) while the CD4+ T cells were polarized into Th17 cells, we observed a tendency toward suppressed IL-17 secretion. ConclusionsHistamine stimulation influences the IL-17 pathway in psoriasis via the fourth histamine receptor subtype, H4R, on CD4+ T cells. The immunomodulatory roles of H4R suggest its potency as a new therapeutic target for obstinate psoriasis.

Clinical Development of Histamine H4 Receptor Antagonists.

The discovery of the histamine H4 receptor (H4R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other histamine receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H4R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H4R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H4R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H4R antagonists can be beneficial in treating atopic dermatitis and pruritus.

SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model of tauopathy

IntroductionTau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. MethodsWe evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22). ResultsSAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. DiscussionLong-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.

Antinociceptive effect of co-administered NMDA and histamine H4 receptor antagonists in a rat model of acute pain.

The histamine H4 receptor (H4R) has attracted a lot of attention in terms of its role in antinociception. The N-Methyl-d-aspartic acid (NMDA) receptor is a well-characterized participant in pain pathways. However, it's influence on H4R signaling is poorly understood. Thus, in the present study we investigated the effect of a selective H4R antagonist JNJ7777120 (25mg/kg) and a NMDA receptor antagonist MK-801 (0.1-10μg) on nociceptive thresholds in a rat acute pain model. The influence of intrathecally (it), intracerebroventricularly (icv) and intraplantarly (ipl) administered MK-801 co-injected with JNJ7777120 administered intraperitoneally (ip) was determined in the modified Randall-Selitto paw pressure, the tail flick and plantar tests. Both ip JNJ7777120 as well as MK-801 delivered it and ipl increased nociceptive pain thresholds. It and ipl pretreatment with MK-801 additively augmented JNJ7777120 mechanical antinociception. A weaker effect was also observed after it co-administration with MK-801 and JNJ7777120 in the tail flick test. Intracerebroventricular MK-801 failed to produce any effect nor did ipl MK-801 in the plantar test. The results show for the first time that the H4R and NMDA receptors play a significant role in antinociception in an acute non-inflammatory pain. Furthermore, the blockage of NMDA receptors at the peripheral and spinal, but not supraspinal sites produces a profound antinociceptive response upon simultaneous H4R antagonism. Thus, this study clearly demonstrates the relevance of NMDA and H4R receptors in the modulation of pain signals and that their role is not exclusively limited to their modulatory activity in inflammatory pain states.

Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human breast cancer cell lines

Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H3 receptor (H3R) plays a role in the proliferation of breast cancer cells. We recently developed the non-imidazole H3R antagonist OUP-186 which exhibited a potent and selective human H3R antagonistic activity as well as no activity against the human histamine H4 receptor (H4R). In this study, we compared the effects of OUP-186 on the proliferation of estrogen receptor negative (ER−) breast cancer cells (MDA-MB-231) and ER+ breast cancer cells (MCF7) to the effects of clobenpropit (potent imidazole-containing H3R antagonist). OUP-186 and clobenpropit suppressed the proliferation of breast cancer cells. The IC50 values at 48 h for OUP-186 and clobenpropit were approximately 10 μM and 50 μM, respectively. Furthermore, OUP-186 potently induced cell death by activating caspase-3/7, whereas cell death was only slightly induced by clobenpropit. In addition, OUP-186 treatment blocked the proliferation increase triggered by 100 μM (R)-(-)-α-methylhistamine (H3R agonist). The use of 4-methylhistamine (H4R agonist) and JNJ10191584 (selective H4R antagonist) did not affect breast cancer proliferation. These results indicate that OUP-186 potently suppresses proliferation and induces caspase-dependent apoptotic death in both ER+ and ER-breast cancer cells.

The histamine H4 receptor: from orphan to the clinic.

The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans.

EFFECT OF ACIDIC AND ALKALINE MEDIUM ON FEXOFENADINE BRANDS USING UV SPECTROPHOTOMETER

Fexofenadine is widely used drug for allergic conditions especially Rhiniti and is a selective histamine H1 receptor antagonist. In our recent research we study the effect of acidic and alkaline medium on four different brands of Fexofenadine, for this the solutions of different brands of Fexofenadine were subjected to neutral,alkaline and acidic medium. When Fexofenadine brands subjected to 0.1 N HCl and 0.1N NaOH for 30 minutes, Fexofenadine brands showed variable availability results. Xanidine and Telefast donot show any change in absorbance in acidic medium but shows a decrease in absorbance in alkaline medium. While Allerga shows a decrease in absorbance in both acidic and alkaline medium. Fexet also shows a decrease in absorbance in acidic medium but shows a increase in absorbance in alkaline medium.

EFFECT OF ACIDIC AND ALKALINE MEDIUM ON FEXOFENADINE BRANDS USING UV SPECTROPHOTOMETER

Fexofenadine is widely used drug for allergic conditions especially Rhiniti and is a selective histamine H1 receptor antagonist. In our recent research we study the effect of acidic and alkaline medium on four different brands of Fexofenadine, for this the solutions of different brands of Fexofenadine were subjected to neutral,alkaline and acidic medium. When Fexofenadine brands subjected to 0.1 N HCl and 0.1N NaOH for 30 minutes, Fexofenadine brands showed variable availability results.

Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy

Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure–activity relationship (SAR) studies of the series culminated in the identification of ((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10μM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.

Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment.

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

Efficacy of epinastine hydrochloride ophthalmic solution in allergic conjunctivitis by conjunctival cedar pollen allergen challenge

BackgroundEpinastine hydrochloride is a selective histamine H1 receptor antagonist that also inhibits IgE receptor-mediated histamine release from mast cells. ObjectiveTo show the superiority of epinastine 0.05% ophthalmic solution (epinastine) to placebo ophthalmic solution (placebo) and noninferiority to olopatadine 0.1% ophthalmic solution (olopatadine) for cedar pollen antigen-induced ocular itching and conjunctival hyperemia. MethodsThe study was conducted in ophthalmologically asymptomatic adult volunteers with seasonal allergic conjunctivitis using a conjunctival allergen challenge test. Subjects were randomized into 3 groups (n = 87) to evaluate superiority to placebo (visits 4 to 6) and 2 groups (n = 86) to evaluate noninferiority to olopatadine (visit 7). At each visit, a single administration of the study medication was instilled at 15 minutes (visit 4), 4 hours (visit 5), 8 hours (visit 6), and 4 hours (visit 7) before the conjunctival allergen challenge test. Ocular itching and conjunctival hyperemia of allergic conjunctivitis were assessed after the conjunctival allergen challenge test. ResultsFor the primary end point, epinastine showed superiority to placebo for the inhibition of ocular itching and conjunctival hyperemia induced at 4 hours after the dose (equivalent to 4-times-daily dosing). For the secondary end points, epinastine significantly inhibited itching and conjunctival hyperemia induced at 15 minutes and 8 hours after the dose (equivalent to 2-times-daily dosing) compared with placebo. In addition, epinastine demonstrated noninferiority to olopatadine for ocular itching and conjunctival hyperemia. No adverse drug reactions or serious adverse events were reported throughout the study, indicating that epinastine has a good safety profile. ConclusionEpinastine is effective and safe for the treatment of allergic conjunctivitis. Trial RegistrationClinicaltrials.gov identifier NCT01363700.

ABSTRACT 745

Background and aims: Dystonia is a neurologic movement disorder, in which causes involuntary muscle contractions and abnormal postures. We reported a case of generalized form of dystonia after taking albendazole and cetirizine. Only one case with albendazole and two cases with cetirizine induced dystonia were previously reported. Methods: Case: A three years and six months old boy who rapidly developed lateral flexion of neck, extension of forearms, adduction and flexion of arms was presented to Pediatric Emergency Department. According to the history, he received only single dose of albendazole and cetirizine 20 hours ago, because of a probable worm infection. Except dystonia, examination was normal. He was managed as dystonia based on history and signs. His symptoms resolved after six hours of intramuscular biperiden treatment. On follow-up visit at the 24th hour of onset, the patient had no complaint. He was thought to be drug-induced dystonia caused by albendazole and/or cetirizine. Conclusions: Antiemetics, antidepressants, dopamine-blocking agents and antipsychotics are the best-known cause of drug induced dystonia. Cetirizine is a high selective histamine H1 receptor antagonist which has dopamine receptor blocking properties in susceptible individuals and may cause dystonic movements. Albendazole affects the cell by inhibiting tubulin polymerization. Two drugs separately or both may be responsible from dystonia in our patient. The metabolic effects of cetirizine are longer acting than effect of albendazole. The patient developed dystonia in nearly 20 hours after taking these two drugs. Therefore, we speculated that in this case cetirizine may lead to dystonia because of its long acting.

Effects Of A Selective Histamine H<sub>4</sub>R Antagonist On Inflammation In A Model Of Carrageenan-Induced Pleurisy In The Rat

The histamine H₄ receptor (H₄R), recently cloned and identified, is a G-protein coupled histamine receptor family expressed in immune cells which plays an important role in inflammation. Recent data evidentiated that H₄R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H₄R antagonist JNJ7777120 (JNJ) in carrageenan-induced pleurisy, an in vivo model of inflammation, well characterized for cellular and molecular mechanisms. Intra-pleural administration of λ-carrageenan (1% w/v in 0.2 ml sterile saline) determined an intense recruitment of leucocytes in pleural exudates and in lung tissues, activated inducible nitric oxide (NO) synthase and cyclooxygenase-2, thus increasing the generation of harmful autacoids such as NO and pro-inflammatory prostaglandins, PgE₂ and 6-ketoPgF(1α), increased cellular and DNA oxidative stress, measured as malondialdehyde and 8-OH-deoxyguanosine and the local generation of IL-1β and TNF-α. Moreover, the activity of caspase-3, an early marker of apoptosis was also activated by λ-carrageenan injection. The pre-treatment with JNJ (5-10 mg Kg⁻¹ b.wt., given intrapleurally), 60 min before carrageenan markedly reduced all the studied parameters. This study clearly demonstrated that histamine H₄R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.

Nizatidine ameliorates gastroparesis in Parkinson's disease: A pilot study

The objective of this work was to perform an open trial of the effects of nizatidine (NZT), a selective histamine H2-receptor antagonist and a cholinomimetic, on gastroparesis in Parkinson's disease (PD) patients, using objective parameters given by a gastric emptying study using a (13) C-sodium acetate expiration breath test. Twenty patients with PD were enrolled in the study. There were 13 men and 7 women; aged 68.0 ± 7.72 years; disease duration 5.50 ± 3.62 years. All patients underwent the breath test and a gastrointestinal questionnaire before and after 3 months of administration of NZT at 300 mg/day. Statistical analysis was performed by Student t test. NZT was well tolerated by all patients and none had abdominal pain or other adverse effects. NZT significantly shortened Tmax ((13) C) (the peak time of the (13) C-dose-excess curve) (P < 0.05). Although this is a pilot study, we found a significant shortening of gastric emptying time after administration of NZT in PD patients.

Famotidine Augmentation in Schizophrenia: Hope or Hype?

J Clin Psychiatry 2013;74(9):e855–e858 (doi:10.4088/JCP.13f08707) © Copyright 2013 Physicians Postgraduate Press, Inc. A medication does not always result in the remission of positive symptoms in patients with schizophrenia. Furthermore, in many patients in whom positive symptoms substantially or completely remit, negative symptoms, cognitive disturbances, and other impairments often remain. Antipsychotic augmentation is one of many strategies to which clinicians turn in an attempt to reduce the burden of these residual symptoms, and famotidine is one of many unconventional augmentation agents that has been studied in this context. Histamine mechanisms may play a role in schizophrenia.1,2 Famotidine is a potent, selective histamine H2 receptor antagonist that poorly penetrates the blood-brain barrier.3,4 Although H2 receptors are present in the brain, there does not seem to be a strong argument made for the involvement of the H2 receptor in schizophrenia; nevertheless, many case reports and small open studies suggest that famotidine may improve outcomes in patients with schizophrenia.

Thioperamide treats neonatal hypoxic-ischemic encephalopathy by postsynaptic H1 receptors.

Thioperamide, a selective histamine H3 receptor antagonist, can increase histamine content in the brain, improve brain edema, and exert a neuroprotective effect. This study aimed to examine the mechanism of action of thioperamide during brain edema in a rat model of neonatal hypoxic-ischemic encephalopathy. Our results showed that thioperamide significantly decreased brain water content and malondialdehyde levels, while significantly increased histamine levels and superoxide dismutase activity in the hippocampus. This evidence demonstrates that thioperamide could prevent oxidative damage and attenuate brain edema following neonatal hypoxic-ischemic encephalolopathy. We further observed that changes in the above indexes occurred after combined treatment of thioperamide with the H1 receptor antagonist, pyrilamine, and the H2 receptor antagonist, tidine. Experimental findings indicated that pyrilamine reversed the effects of thioperamide; however, cimetidine had no significant influence on the effects of thioperamide. Our present findings suggest that thioperamide can increase brain histamine content and attenuate brain edema and oxidative damage by acting in combination with postsynaptic H1 receptors in a rat model of neonatal ic-ischemic encephalopathy.

Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

This Letter describes the asymmetric synthesis of the four stereoisomers (8a–8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a–8d were determined. Stereoisomer 8c (2S,3′S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.

Tu2116 The Effects of Jnj 7777120, a Selective Histamine H4 Receptor Antagonist, on Visceromotor Responses in a Rat Model for Post-Inflammatory Visceral Hypersensitivity

Tu2116 The Effects of Jnj 7777120, a Selective Histamine H4 Receptor Antagonist, on Visceromotor Responses in a Rat Model for Post-Inflammatory Visceral Hypersensitivity

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients.

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part I)

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.