Brenda K. Trail

GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H3 receptor antagonist with high affinity for human (pKi = 9.59 –9.90) and rat (pKi = 8.51–9.17) H3 receptors. GSK189254 is >10,000-fold selective for human H3 receptors versus other targets tested, and it exhibited potent functional antagonism (pA2 = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC50 = 8.20 versus basal guanosine 5′-O-(3-[35S]thio)triphosphate binding] at the human recombinant H3 receptor. In vitro autoradiography demonstrated specific [3H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H3 binding was detected in medial temporal cortex samples from severe cases of Alzheimers disease, suggesting for the first time that H3 receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(–)-α-methyl[imidazole-2,5(n)-3H]histamine dihydrochloride ([3H]R-α-methylhistamine) binding (ED50 = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3–3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H3 receptors was demonstrated by blockade of R-α-methylhistamine-induced dipsogenia in rats (ID50 = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimers disease and other cognitive disorders.

LABORAS™: Initial pharmacological validation of a system allowing continuous monitoring of laboratory rodent behaviour

A newly developed apparatus for automated behavioural analysis, Laboratory Animal Behaviour Observation, Registration and Analysis System (LABORAS), has been further validated with respect to the ability of the system to detect the pharmacodynamic effects of standard pharmacological tools. Data were obtained from rats administered with mCPP (reversal with SB242084), 8-OH-DPAT (reversal with WAY100635), amphetamine (reversal with haloperidol) and angiotensin, with the focus on locomotor activity, feeding and drinking behaviours. The data captured and analysed by LABORAS, suggests that the automated system is able to detect pharmacologically induced changes in behaviour, reliably and efficiently, with a significant reduction in the number of animals required, and reduced operator input.

Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.

Postsynaptic 5-HT1B receptors modulate electroshock-induced generalised seizures in rats

1 Although an important regulatory role for serotonin (5‐HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5‐HT receptor subtypes on seizure modulation. 2 The aim of the present study was to investigate the role of 5‐HT1A, 1B and 1D receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3 The mixed 5‐HT receptor agonists SKF 99101 (5–20 mg kg−1 i.p.) and RU 24969 (1–5 mg kg−1 i.p.), 0.5 h pretest, both produced marked dose‐related increases in seizure threshold. These agents share high affinity for 5‐HT1A, 1B and 1D receptors. 4 Antiseizure effects induced by submaximal doses of these agonists were maintained following p‐chlorophenylalanine (150 mg kg−1 i.p. × 3 days)‐induced 5‐HT depletion. 5 The anticonvulsant action of both SKF 99101 (15 mg kg−1 i.p.) and RU 24969 (2.5 mg kg−1 i.p.) was dose‐dependently abolished by the selective 5‐HT1B receptor antagonist SB‐224289 (0.1–3 mg kg−1 p.o., 3 h pretest) but was unaffected by the selective 5‐HT1A receptor antagonist WAY 100635 (0.01–0.3 mg kg−1 s.c., 1 h pretest). This indicates that 5‐HT1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6 In addition, the ability of the 5‐HT1B/1D receptor antagonist GR 127935 (0.3–3 mg kg−1 s.c., 60 min pretest) to dose‐dependently inhibit SKF 99101‐induced elevation of seizure threshold also suggests possible downstream involvement of 5‐HT1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5‐HT1D receptor antagonist. 7 Overall, these data demonstrate that stimulation of postsynaptic 5‐HT1B receptors inhibits electroshock‐induced seizure spread in rats.

Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.

This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimers disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.

The discovery of the benzazepine class of histamine H3 receptor antagonists

This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.

P4-327: Effects of the novel 5-HT6 SB-742457 antagonist and the cholinesterase inhibitor donepezil in models of cognition

related to aging, Alzheimer’s disease (AD) and Schizophrenia. Thus serotonergic system became a potential target for the treatment of memory dysfunction. Methods: Our effective lead generation and optimization methods have resulted in a potent 5-HT6 receptor antagonist SUVN-502 with Ki of 1.71 nM. SUVN-502 exhibited antagonist like inhibition with EC50 of 0.103 M when tested for functional activity. SUVN-502 has more than 100 fold selectivity against the related GPCRs. The effective optimization of its critical physico-chemical properties has lead to oral bioavailability (31%) and brain penetration index (1.48). Results: SUVN-502 was effective in animal models of cognition. SUVN-502 reversed the age induced memory deficit in Morris water maze and novel object recognition task (NORT). SUVN-502 also reversed the spatial and working memory deficit induced by MK-801 and scopolamine in Morris water maze, NORT and radial arm maze task. The effective dose range of SUVN-502 in the above animal models was between 3 to 10 mg/kg. p.o. Brain microdialysis studies in rats with SUVN-502 showed significant increase in brain acetylcholine and glutamate levels correlating to the in vivo memory models. Conclusions: SUVN-502 has been identified as a candidate for clinical development for the symptomatic treatment of Alzheimer’s disease. SUVN-502 has completed all regulatory safety and toxicity studies to enter to human Phase-I clinical trials in 2008.