Development and SAR of functionally selective allosteric modulators of GABAA receptors

Alhambra, Cristóbal; Becker, Chris; Blake, Timothy J.; Chang, Amy Hui-Fang; Damewood, James; Daniels, Thalia; Dembofsky, Bruce T.; Gurley, David; Hall, James Edwin; Herzog, Keith J.; Horchler, Carey L.; Ohnmacht, Cyrus J.; Schmiesing, Richard J.; Dudley, Amanda; Ribadeneira, Maria; Knappenberger, Katherine S; Maciag, Carla; Stein, Mark M.; Chopra, Maninder; Liu, Xiaodong F.; Christian, Edward P.; Arriza, Jeffrey L.; Chapdelaine, Marc J.

doi:10.1016/j.bmc.2011.03.035

Cited by 43 publications

(48 citation statements)

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“…Fig. 1, Alhambra et al 2011). Both compounds exert their function selectively via GABA A receptor subunits as characterized by high in vitro affinity to the α1, α2, and α3 subunits and low affinity to the α5 subunit (Suppl.…”

Section: Introductionmentioning

confidence: 92%

“…Table 1). In preclinical models, these compounds have potent anxiolytic-like effects without sedation and induce a distinct pharmacoEEG signature (Alhambra et al 2011; Christian et al 2015). Examination of pharmacodynamic effects in phase I clinical trials has shown a novel pattern of effects on EEG (reduction in delta and theta bands) by AZD7325 and AZD6280, as well as effects on saccadic peak velocity, a suggested marker of anxiolysis (Chen et al 2014, 2015).…”

Section: Introductionmentioning

confidence: 99%

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GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

et al. 2016

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RationaleSedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects.ObjectivesThe current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability.MethodTwo PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests.ResultsThe [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively.ConclusionHigh GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4506-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

et al. 2016

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“…AZD6280 (4-Amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide) 11,12 is a novel, subtype-selective GABA A receptor modulator, which in contrast to BZDs, exerts minimal efficacy at α 1 -subunit containing GABA A receptors. Although AZD6280 has relatively high (±standard deviation, SD) binding affinity to the α 1 (Ki = 0.5 ± 0.2 nM), α 2 (Ki = 21 ± 5 nM), and α 3 (Ki = 31 ± 17 nM) GABA A subunits, its affinity for the α 5 subunit is much lower (Ki = 1680 ± 650 nM).…”

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confidence: 99%

AZD6280, a Novel Partial γ-Aminobutyric Acid A Receptor Modulator, Demonstrates a Pharmacodynamically Selective Effect Profile in Healthy Male Volunteers

Chen

Jacobs

Kam

et al. 2015

Journal of Clinical Psychopharmacology

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The SPV responses to AZD6280 suggest potential concentration-related anxiolytic effects, whereas the smaller SPV-normalized effects of AZD6280 on various non-SPV pharmacodynamic parameters suggest a more favorable side effect profile compared to lorazepam. Overall, the pharmacodynamic profile of AZD6280 matches the pharmacological specificity and selectivity of this compound at the α2,3 γ-aminobutyric acid A receptor subtypes.

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“…Selective allosteric modulators of GABA Aa2,3 were discovered and developed at AstraZeneca, aiming for anxiety disorder treatment with benzodiazepine-like efficacy and fast onset but reduced sedation and abuse liabilities (Alhambra et al, 2011;Jucaite et al, 2017). Among a few candidate drugs discovered, 4-amino-8-(2-fluoro-6-methoxyphenyl)-N-propylcinnoline-3-carboxamide (AZD7325) was advanced to Phase IIb clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Late-occurring and Long-circulating Metabolites of GABA_A_α_2,3 Receptor Modulator AZD7325 Involving Metabolic Cyclization and Aromatization: Relevance to MIST Analysis and Application for Patient Compliance

Artelsmair

Elmore

et al. 2018

Drug Metab Dispos

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AZD7325 [4-amino-8-(2-fluoro-6-methoxyphenyl)-N-propylcinnoline-3-carboxamide] is a selective GABA Aa2,3 receptor modulator intended for the treatment of anxiety disorders through oral administration. An interesting metabolic cyclization and aromatization pathway led to the tricyclic core of M9, i.e., 2-ethyl-7-(2-fluoro-6-methoxyphenyl)-pyrimido [5,4-c]cinnolin-4(3H)-one. Further oxidative metabolism generated M10 via O-demethylation and M42 via hydroxylation. An authentic standard of M9 was synthesized to confirm the novel structure of M9 and that of M10 and M42 by liver microsomal incubation of the M9 standard. Metabolites M9, M10, and M42 were either minor or absent in plasma samples after a single dose; however, all became major metabolites in human and preclinical animal plasma after repeated doses and circulated in humans longer than 48 hours after the end of seven repeated doses. The absence of these long circulating metabolites from selected patients' plasma samples was used to demonstrate patient noncompliance as the cause of unexpected lack of drug exposure in some patients during a Phase IIb outpatient clinical study. The observation of late-occurring and longcirculating metabolites demonstrates the need to collect plasma samples at steady state after repeated doses when conducting metabolite analysis for the safety testing of drug metabolites. All 12 major nonconjugate metabolites of AZD7325 observed in human plasma at steady state were also observed in dog, rat, and mouse plasma samples collected from 3-month safety studies and at higher exposures in the animals than humans. This eliminated concern about human specific or disproportional metabolites.

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Development and SAR of functionally selective allosteric modulators of GABAA receptors

Cited by 43 publications

References 11 publications

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

AZD6280, a Novel Partial γ-Aminobutyric Acid A Receptor Modulator, Demonstrates a Pharmacodynamically Selective Effect Profile in Healthy Male Volunteers

Late-occurring and Long-circulating Metabolites of GABA_A_α_2,3 Receptor Modulator AZD7325 Involving Metabolic Cyclization and Aromatization: Relevance to MIST Analysis and Application for Patient Compliance

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Development and SAR of functionally selective allosteric modulators of GABAA receptors

Cited by 43 publications

References 11 publications

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

AZD6280, a Novel Partial γ-Aminobutyric Acid A Receptor Modulator, Demonstrates a Pharmacodynamically Selective Effect Profile in Healthy Male Volunteers

Late-occurring and Long-circulating Metabolites of GABAAα2,3 Receptor Modulator AZD7325 Involving Metabolic Cyclization and Aromatization: Relevance to MIST Analysis and Application for Patient Compliance

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Late-occurring and Long-circulating Metabolites of GABA_A_α_2,3 Receptor Modulator AZD7325 Involving Metabolic Cyclization and Aromatization: Relevance to MIST Analysis and Application for Patient Compliance