The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders

Poulter, Simon; Austin, Nigel; Armstrong, Rachel; Barnes, Matt; Bucknell, S.J.; Higueruelo, Alícia P.; Banjaree, Joydeep; Mead, Andy N.; Mould, Richard F.; MacSweeney, Cliona; O’Brien, Alistair; Stott, Lisa; Watson, Stephen P.

doi:10.1021/acsmedchemlett.3c00052

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…Arena Pharmaceuticals disclosed a series of indoline-4-carboxamides as GPR52 agonists, exemplified by a representative compound 4a . Recently, Sosei Heptares reported an additional series of GPR52 agonists with a similar pharmacophore, exemplified by HTL0041178 . Phase I clinical trials have begun with compound HTL0048149 (structure not disclosed) as the first-in-class GPR52 agonist from Sosei Heptares for the treatment of SZ positive, negative, and cognitive symptoms, potentially without the adverse effects accompanied by currently available antipsychotics .…”

Section: Introductionmentioning

confidence: 99%

“…27 Recently, Sosei Heptares reported an additional series of GPR52 agonists with a similar pharmacophore, exemplified by HTL0041178. 28 Phase I clinical trials have begun with compound HTL0048149 (structure not disclosed) as the first-in-class GPR52 agonist from Sosei Heptares for the treatment of SZ positive, negative, and cognitive symptoms, potentially without the adverse effects accompanied by currently available antipsychotics. 29 Some additional GPR52 modulators have been disclosed in recent patents.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists

Murphy,

Wang,

Ali

et al. 2024

J. Med. Chem.

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Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 β-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists

Murphy,

Wang,

Ali

et al. 2024

J. Med. Chem.

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show abstract

“…Most recently, Sosei‐Heptares have developed a number of GPR52 agonists around a pyridine core. Whilst cAMP potencies of the series vary greatly, the series exemplar, HTL‐0041178, has an excellent pharmacokinetic profile with a brain: plasma ratio of >2, >50% bioavailability across multiple species and long duration of action (>12 hr) (Poulter et al, 2023). Sosei‐Heptares plans to enter phase I trials in the first half of 2023.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into orphan G protein‐coupled receptors relevant to schizophrenia

Lu,

Hatzipantelis,

Langmead

et al. 2023

British J Pharmacology

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Schizophrenia remains a sizable socio‐economic burden that continues to be treated with therapeutics based on 70‐year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non‐dopaminergic G protein‐coupled receptors (GPCRs) have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non‐dopaminergic GPCR‐targeting drugs, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie outside of the dopaminergic space. Despite the potential for muscarinic receptor‐ (and other well‐characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on‐target side effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia‐relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally expressed orphan GPCRs: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.

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Orphan GPR52 as an emerging neurotherapeutic target

Ali,

Wang,

Murphy

et al. 2024

Drug Discovery Today

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The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders

Cited by 5 publications

References 16 publications

Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists

Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists

Molecular insights into orphan G protein‐coupled receptors relevant to schizophrenia

Orphan GPR52 as an emerging neurotherapeutic target

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