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

Wilson, David M.; Apps, James; Bailey, N.T.; Bamford, Mark J.; Beresford, I.J.M.; Brackenborough, Kim; Briggs, Michael A.; Brough, Stephen; Calver, Andrew R.; Crook, Barry; Davis, Rebecca K.; Davis, Robert P.; Davis, Susannah; Dean, David K.; Harris, Leanne; Heslop, Teresa; Holland, Vicky; Jeffrey, Philip D.; Panchal, Terrance A.; Parr, Christopher A.; Quashie, Nigel; Schogger, Joanne; Sehmi, Sanjeet S.; Stean, Tania O.; Steadman, Jon G.A.; Trail, Brenda; Wald, Jeffrey; Worby, Angela; Takle, Andrew K.; Witherington, Jason; Medhurst, Andrew D.

doi:10.1016/j.bmcl.2013.09.090

Cited by 22 publications

(14 citation statements)

References 23 publications

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“…In the present study, the in vivo affinity of GSK239512 for the human H 3 receptor, equivalent to a negative log of the dissociation constant (p K ), was estimated as 11.3, that is K D = 4.50 × 10 −12 M. This estimate, which takes into account a plasma‐free fraction ( f P ) of 0.25 for GSK239512 and which presumes a one‐to‐one ratio of free concentration between brain and plasma, is more than an order of magnitude higher than that measured in vitro for the same compound, assuming 100% free compound in the assay (p K = 9.9–9.7; K D = 1.26‐2.00 × 10 −10 M; Wilson et al ., ). It might be noted that the structurally similar compound, GSK189254, shows a similar discrepancy in humans between in vivo estimates of p K , determined using PET (p K = 11.0, K D = 1.00 × 10 −11 M Ashworth et al ., ), compared with an in vitro p K of 9.9–9.6 ( K D = 1.26–2.51 × 10 −10 M Medhurst et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…[ 11 C]GSK189254 was prepared by [ 11 C]-methylation of the carboxamide precursor GSK185071B as previously described (Wilson et al, 1994). The chemical structures of GSK189254 and GSK239512 were published by Medhurst et al (2007) and Wilson et al (2013), respectively.…”

Section: Radiochemistrymentioning

confidence: 99%

“…The plasma-free fraction (fP) of GSK239512 is 0.25 (Wilson et al, 2013) and its molecular weight is 377.49. The estimated plasma EC50 of 0.0068 ng·mL −1 therefore corresponds to a free KD in vivo of 4.50 × 10 −12 M, that is pK = 11.3.…”

Section: Profiles (Percentiles Represented By the Dotted Line Onmentioning

confidence: 99%

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Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Ashworth

Berges

Rabiner

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThis study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers. EXPERIMENTAL APPROACHPET scans were obtained after i.v. administration of the H3-specific radioligand [ 11 C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan. KEY RESULTSFollowing administration of GSK239512, there was a reduction in the brain uptake of [ 11 C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL . This corresponds to a free concentration of 4.50 × 10 −12 M (pK = 11.3). CONCLUSIONS AND IMPLICATIONSThe affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose. Abbreviations

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Section: Discussionmentioning

confidence: 97%

Section: Radiochemistrymentioning

confidence: 99%

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Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Ashworth

Berges

Rabiner

et al. 2014

British J Pharmacology

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“…Another two H3R antagonists, namely GSK-189254 and GSK-239512, have been described as potent, selective, and highly brain penetrant antagonists with proven effectiveness in a number of animal experiments, including attentional and memory models (Figure 10, Table 1) [53,59,[91][92][93][94][95][96][97]. Interestingly, GSK-239512 has completed phase 1 clinical trial, and the results suggest a modest efficacy in mild-moderate AD patients (ClinicalTrials.gov trial registration number: NCT00675090).…”

Section: Alzheimer's Diseasementioning

confidence: 94%

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Sadek

Saad

Sadeq

et al. 2016

Behavioural Brain Research

135

129

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“…; Wilson et al. ). While prior work has used oral gavage to deliver the drug, we found that this drug delivery method disrupted activity rhythms in C57 mice (data not shown).…”

Section: Methodsmentioning

confidence: 98%

Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease

Whittaker

Wang

Loh

et al. 2017

Pharmacology Res & Perspec

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Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine‐3 receptor (H3R) antagonist/inverse agonist 6‐[(3‐cyclobutyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐7‐yl)oxy]‐N‐methyl‐3‐pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD.

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

Cited by 22 publications

References 23 publications

Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease

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

Cited by 22 publications

References 23 publications

Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease

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Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Unexpectedly high affinity of a novel histamine H₃ receptor antagonist, GSK239512, in vivo in human brain, determined using PET