Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach

Ledneczki, István; Tapolcsányi, Pál; Gábor, Eszter; Visegrády, András; Vass, Márton; Éles, János; Holm, Patrik; Horváth, Anita; Pocsai, Anikó; Mahó, Sándor; Greiner, István; Krámos, Balázs; Béni, Zoltán; Kóti, János; Káncz, Anna E.; Thán, Márta; Kolok, Sándor; Laszy, Judit; Balázs, Ottilia; Bugovits, Gyula; Nagy, József; Vastag, Mónika; Szájli, Ágota; Bozó, Éva; Lévay, György; Lendvai, Balázs; Némethy, Zsolt

doi:10.1016/j.ejmech.2021.113189

Cited by 9 publications

(20 citation statements)

References 31 publications

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“…Des-amino pyrrole analogs 22 and 23 described in Table were obtained upon treatment of the amino nitrile intermediate 64 with t BuONO, and the resulting diazonium was either protonolyzed to yield intermediate 83 or treated with CuCl to obtain chlorinated compound 84 , respectively, as depicted in Scheme . Hydrolysis of the nitrile of intermediate 83 to the carboxamide upon treatment with sulfuric acid, followed by methoxy deprotection upon treatment with BBr 3 , yielded analogs 22 .…”

Section: Resultsmentioning

confidence: 99%

“…The mixture was stirred at rt for 15 min and then refluxed for 4 h. The volatiles were evaporated under reduced pressure, and the resulting residue was poured by portion in cold aq. 1 M HCl to give a yellow precipitate that was filtered and washed with water to afford a mixture of 2-( 5 [3,2-b]quinoxaline-3-carboxamide (26). Following the procedure used to prepare 76, a solution of 93 and 94 (5.0 g, 11.8 mmol) in sulfuric acid (50 mL) was stirred for 1 h at rt to provide a mixture of 2-amino-8-bromo-1-(3methoxy-2,6-dimethylphenyl)pyrrolo [3,2-b]quinoxaline-3-carboxamide and 2-amino-5-bromo-1-(3-methoxy-2,6-dimethylphenyl)pyrrolo [2,3-b]quinoxaline-3-carboxamide (5.2 g, quantitative yield, ESI MS m/z 442.0 [M + H] + ) as a yellow solid.…”

Section: -Amino-8-bromo-1-(3-methoxy-26-dimethylphenyl)pyrrolo-[32-b]...mentioning

confidence: 99%

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Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

et al. 2022

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PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

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Section: Resultsmentioning

confidence: 99%

Section: -Amino-8-bromo-1-(3-methoxy-26-dimethylphenyl)pyrrolo-[32-b]...mentioning

confidence: 99%

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

et al. 2022

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“…A 1°scaffold hopping approach reported by Ledneczki and co-workers was used in the development of positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (α7 nAChRs). 54 α7 nAChRs are implicated in cognitive processes and have been validated with in vivo models as potential drug targets for conditions such as Alzheimer's disease and schizophrenia. 55 Among various other SAR explorations of pendant groups, Ledneczki and co-workers performed heterocyclic replacements (Figure 7) of the pyrrole core of 19 with various other 5-membered aromatic heterocycles such as a pyrazole (20), furan (21), and oxazole (22).…”

Section: Recent Scaffold Hopping Highlights In Cns Drugmentioning

confidence: 99%

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

et al. 2022

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The concept of bioisosterism and the implementation of bioisosteric replacement is fundamental to medicinal chemistry. The exploration of bioisosteres is often used to probe key structural features of candidate pharmacophores and enhance pharmacokinetic properties. As the understanding of bioisosterism has evolved, capabilities to undertake more ambitious bioisosteric replacements have emerged. Scaffold hopping is a broadly used term in the literature referring to a variety of different bioisosteric replacement strategies, ranging from simple heterocyclic replacements to topological structural overhauls. In this work, we have highlighted recent applications of scaffold hopping in the central nervous system drug discovery space. While we have highlighted the benefits of using scaffold hopping approaches in central nervous system drug discovery, these are also widely applicable to other medicinal chemistry fields. We also recommend a shift toward the use of more refined and meaningful terminology within the realm of scaffold hopping.

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“…To explore the SAR of the phenyl ring in the tricyclic scaffold, all four possible bromophenyl regioisomers of analog 6 were prepared (compounds 26-29) to enable further diversification of each position by transition metal-mediated transformations. Although all four bromo analogs (26)(27)(28)(29) displayed low nanomolar potencies in the enzymatic assay, compound 29 was found to have superior potency in the cell-based activity assay (Table 4). The three most promising bromo regioisomers (26, 28, and 29) were each derivatized to provide representative nitrile, pyrazole and cyclopentene analogs 30-38.…”

Section: Compound Structure-activity-relationships and Optimizationmentioning

confidence: 99%

“…The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 20 to 60% EtOAc in hexanes to provide a mixture of 93 and 94 (8.9g, 72% yield) as an orange solid. ESI MS m/z 424.1 (26). Following the procedure used to prepare 76, a solution of 93 and 94 (5.0g, 11.8 mmol) in sulfuric acid (50 mL) was stirred for 1 h at RT to provide a mixture of 2-amino-8-bromo-1-(3-methoxy-2,6dimethyl-phenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide and 2-amino-5-bromo-1-(3-methoxy-2,6dimethyl-phenyl)pyrrolo[2,3-b]quinoxaline-3-carboxamide (5.2 g, quantitative yield, ESI MS m/z 442.0 [M + H] + ) as a yellow solid.…”

Section: -Aminomentioning

confidence: 99%

Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

Szychowski

Papp

Dietrich

et al. 2022

Preprint

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PKMYT1 is an important regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1 in the treatment of cancer. To address this need we conducted a focused screening effort that identified compound 1 as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol dramatically increased potency on PKMYT1. These dimethylphenol analogs were found to exist as Type III atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design aided by co-crystal structures of several analogs enabled optimization of cell-based potency and kinase selectivity. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1 with favorable pharmacokinetics. RP-6306 inhibits the phosphorylation of CDK1 Thr14 in vivo in tumor tissue and inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials (NCT04855656) for treatment of various solid tumors.

show abstract

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach

Cited by 9 publications

References 31 publications

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

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