Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40)

Zahanich, Ihor; Kondratov, Ivan S.; Naumchyk, Vasyl; Kheylik, Yuri; Платонов, М. О.; Zozulya, Sergey; Krasavin, Mikhail

doi:10.1016/j.bmcl.2015.06.018

Cited by 31 publications

(27 citation statements)

References 33 publications

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“…agonists, 8 we designed 1,2,4-oxadiazole containing spirocyclic piperidine building blocks 3p-r. The synthesis of the latter was achieved via a multistep reaction sequence which included HornerWadsworth-Emmons olefination, reduction of the ,-unsaturate ester, alkaline hydrolysis of its saturated counterpart to provide common carboxylic acid starting material 11.…”

Section: Methodsmentioning

confidence: 99%

“…The residue was purified by column chromatography on silica gel using 015% ethyl acetate in hexanes as eluent to provide the title compound. 8,166.6,159.9,143.0,141.7,129.9,129.6,127.9,127.0,118.1,115.1,80.3,69.4,52.2,28.2;MS m/z 369.6 (M + H + ).…”

Section: Methyl 4-({4-[(1e)-3-tert-butoxy-3-oxoprop-1-en-1-yl]phenoxymentioning

confidence: 99%

“…MS m/z 170.0 (M+H + ). 8,129.8,126.7 (q,J = 31.6 Hz),125.0 (q,J = 3.81 Hz),122.6,79.2,68.1,60.0,42.2,41.7,35.3,31.7,31.1,25.5. MS m/z 314.0 (M+H + ).…”

Section: -Methyl-1-oxa-9-azaspiro[55]undecane Hydrochloride (3h)mentioning

confidence: 99%

“…1,131.59,130.2 (d,J = 8.3 Hz),129.3,129.2,127.8,123.0 (d,J = 2.7 Hz),114.6,113.9 (d,J = 20.9 Hz),113.7 (d,J = 21.4 Hz),70.6,68.7,68.6,68.0,58.4,58.3,46.9,46.8,35.5,33.5,31.6,30.7,29.5,28.3. HRMS (ESI) 8,156.5,143.0,138.5,133.1,131.6,129.3,129.2,127.9 (q,J = 13.8 Hz),127.8,127.6,125.1 (q,J = 3.8 Hz),124.3 (q,J = 271.9 Hz),114.5,70.8,68.7,68.6,68.0,58.3,58.3,46.9,46.8,40.8,35.5,33.5,31.6,29.5,28.3 HRMS (ESI) …”

Section: -[4-({4-[(4-ethoxy-1-oxa-9-azaspiro[55]undec-9-yl)methyl]bmentioning

confidence: 99%

“…On the other hand increasing the polarity (i. e. increasing the total polar surface area or lowering the LogP) of FFA1 agonists could provide the solution to the toxicity problem. Recently, we reported potent and selective FFA1 agonists based on containing 1,3-oxazole, 1,2,4-oxadiazole 8 and 1,2,4-thiadiazole [9][10] grafted onto or replacing the phenyl ring of the 3- [4-(benzyloxy)phenyl]propanoic acid core, which mimics the fatty acid endogenous ligands of the receptor and is present in TAK-875 and other advanced compounds of this class (such as Amgen's AMG-837, 11 and Eli Lilly's Besides the heterocyclic appendage 8 or scaffold hopping [9][10] approach realized in our previous studies, we became intrigued by the structure of LY2881835 and the presence of a basic amine center, in combination with the spirocyclic motif, in its periphery. Both aspects appeared quite appealing from the drug design standpoint.…”

Section: Introductionmentioning

confidence: 99%

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Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

Krasavin¹,

Lukin²,

Bagnyukova³

et al. 2016

Bioorganic & Medicinal Chemistry

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The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists containing the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC 50 = 55 nM) was achieved.Four lead compounds (EC 50 range 55 -410 nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F = 10.3%) and plasma levels achieved on oral administration.

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Section: Methodsmentioning

confidence: 99%

Section: Methyl 4-({4-[(1e)-3-tert-butoxy-3-oxoprop-1-en-1-yl]phenoxymentioning

confidence: 99%

“…MS m/z 170.0 (M+H + ). 8,129.8,126.7 (q,J = 31.6 Hz),125.0 (q,J = 3.81 Hz),122.6,79.2,68.1,60.0,42.2,41.7,35.3,31.7,31.1,25.5. MS m/z 314.0 (M+H + ).…”

Section: -Methyl-1-oxa-9-azaspiro[55]undecane Hydrochloride (3h)mentioning

confidence: 99%

Section: -[4-({4-[(4-ethoxy-1-oxa-9-azaspiro[55]undec-9-yl)methyl]bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

Krasavin¹,

Lukin²,

Bagnyukova³

et al. 2016

Bioorganic & Medicinal Chemistry

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Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK‐875)

Lukin

Bakholdina

Zhurilo

et al. 2020

Archiv der Pharmazie

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Three types of heterocyclic moieties—piperidines fused to a heteroaromatic moiety—were explored as potential periphery motifs for the pharmacophoric core of fasiglifam (TAK‐875), with fasiglifam being the most advanced agonist of free fatty acid receptor 1, a promising target for therapeutic intervention in type 2 diabetes. Several observed structure–activity relationship trends were corroborated by in silico docking results. Balanced selection based on potency and Caco‐2 permeability advanced six compounds to cellular efficacy tests (glucose‐stimulated insulin secretion in rat insulinoma INS1E cells). This led to the nomination of compound 16a (LK1408, 3‐[4‐({4‐[(3‐{[(2‐fluorobenzyl)oxy]methyl}‐1‐methyl‐1,4,6,7‐tetrahydro‐5H‐pyrazolo[4,3‐c]pyridin‐5‐yl)methyl]benzyl}oxy)phenyl]propanoic acid hydrochloride) as the lead for further development.

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Diastereoselective Opening of Bridged Anhydrides by Amidoximes Providing Access to 1,2,4‐Oxadiazole/Norborna(e)ne Hybrids

et al. 2019

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A unique example of the one‐pot trans‐diastereoselective reaction of meso‐tricyclic anhydrides is reported. The process involves anhydride ring opening by an amidoxime and the sequential cis‐ to trans‐ epimerization/cyclodehydration of the O‐acylamidoxime intermediate. The resulted 1,2,4‐oxadiazole/norborna(e)ne hybrids are obtained in moderate to good yields and > 95 % diastereomeric excess without any additional purifications. These compounds are interesting not only for drug discovery but for other chemistry‐related fields due to the presence of two easily modifiable moieties.

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Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40)

Cited by 31 publications

References 33 publications

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK‐875)

Diastereoselective Opening of Bridged Anhydrides by Amidoximes Providing Access to 1,2,4‐Oxadiazole/Norborna(e)ne Hybrids

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