ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase

Dato, Florian M.; Neudörfl, Jörg‐Martin; Gütschow, Michael; Goldfuß, Bernd; Pietsch, Markus

doi:10.1016/j.bioorg.2019.103352

Cited by 11 publications

(7 citation statements)

References 58 publications

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“…In contrast, electron withdrawing groups (EWG) were preferred on the meta-position (F (7), Cl (8), Br (11), CF3 (13), but not nitro (17). The electron withdrawing effect was absent or less pronounced on the para-position (Cl (9), Br (12) or CF3 (14). Of interest, a phenyl substitution (18) was tolerated at the meta-position, suggesting the presence of a hydrophobic pocket.…”

Section: Hit Optimization Of -Sulfinyl Esters As Highly Potent Magl ...mentioning

confidence: 98%

“…8,9 Reversible inhibitors may avoid these unfavorable side-effects. [10][11][12][13][14][15][16][17][18][19] To harness the therapeutic potential of MAGL, a high-throughput screen (HTS) was previously performed to identify novel reversible MAGL inhibitors. A natural substrate assay was employed that utilizes an enzymatic cascade to convert glycerol, a metabolite produced by MAGL, into a fluorescent signal.…”

Section: Introductionmentioning

confidence: 99%

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Structure-activity relationship studies of arylsulfoxides as reversible monoacylglycerol lipase inhibitors

Jiang,

Huizenga,

Mohr

et al. 2023

Preprint

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Monoacylglyerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury and pain, multiple sclerosis and cancer. Previously, we reported LEI-515, an arylsulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models without inducing central nervous system (CNS)-mediated adverse effects. Here, we describe the structure-activity relationship (SAR) of arylsulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high throughput screening (HTS) hit 1 yielded ± 43 with high potency (pIC50 = 8.5 ± 0.1). However, ± 43 was not metabolically stable due to its ester moiety, which was required for affinity. Replacing the ester group with α-CF2 ketone as a bio-isoster led to the identification of compound ± 74 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

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Section: Hit Optimization Of -Sulfinyl Esters As Highly Potent Magl ...mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Structure-activity relationship studies of arylsulfoxides as reversible monoacylglycerol lipase inhibitors

Jiang,

Huizenga,

Mohr

et al. 2023

Preprint

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“…1 Hz, 3H). 13 (12). The title compound was synthesized using 1-(4-bromophenyl)piperazine (23 mg, 0.10 mmol, 1 equiv), 4-((2-ethoxy-2-oxoethyl)sulfinyl)-3-nitrobenzoic acid (30 mg, 0.10 mmol, 1 equiv), oxalyl chloride (13.90 mg, 0.11 mmol, 1.1 equiv), and DiPEA (39 mg, 0.30 mmol, 3 equiv) according to general procedure A in a yield of 31 mg (0.06 mmol, 61%).…”

Section: Ethyl 2-((4-((s)-3-methyl-4-(m-tolyl)piperazine-1-carbonyl)-...mentioning

confidence: 99%

“…In contrast, electron-withdrawing groups (EWG) were preferred on the meta-position (F (7), Cl (8), Br (11), CF 3 (13), but not nitro (17). The electronwithdrawing effect was absent or less pronounced on the para-position (Cl (9), Br (12), or CF 3 (14). Of interest, a phenyl substitution (18) was tolerated at the meta-position, suggesting the presence of a hydrophobic pocket.…”

Section: ■ Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors

Jiang,

Huizenga,

Mohr

et al. 2024

J. Med. Chem.

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Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515, an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure−activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43. However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF 2 ketone led to the identification of compound ±73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

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“…The compound J1 , 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea, was the most active inhibitor. This class of compounds was shown to interact with MAGL in a reversible manner, exhibiting a mixed-type inhibition with a predominant competitive behavior [ 56 ]. 2-sulfonacetamide ( J4 ) and squareamide ( J3 ) derivatives possessed lower IC 50 .…”

Section: Magl Inhibitorsmentioning

confidence: 99%

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

et al. 2021

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Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

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ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase

Cited by 11 publications

References 58 publications

Structure-activity relationship studies of arylsulfoxides as reversible monoacylglycerol lipase inhibitors

Structure-activity relationship studies of arylsulfoxides as reversible monoacylglycerol lipase inhibitors

Structure–Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

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