Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists

Bobiļeva, Olga; Bokaldere, R. P.; Gailite, Vija; Kaula, Ilze; Ikaunieks, Martins; Дубурс, Г.; Petrovska, Ramona; Mandrika, Ilona; Kloviņš, Jānis; Loza, Einars

doi:10.1016/j.bmc.2014.05.011

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…(2-(Naphthalen-2-yl)cyclopropyl)methanol. 38 Yield: 89% (2.43 g), yellow oil, cis/trans = 4:5. 1 H and 13 C{ 1 H} spectroscopic data are identical to those described in the literature [ref 38].…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Donor–Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes

et al. 2020

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The bicyclopropyl system activated by incorporation of donor and acceptor groups in the presence of Lewis acids was used as a synthetic equivalent of 1,6-zwitterions. Opening of both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates (D–A bicyclopropyl, ABCDs) in the presence of GaI3 + Bu4N+GaI4 – results in 5-iodo-5-arylpent-2-enylmalonates as products of HI formal 1,6-addition to the bicyclopropyl system. The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl or alkyl acetylenes as 1,6-zwitterion interceptors allows the alkyl substituent to be grown to give the corresponding acyclic 7-chloro(bromo)-hepta-2,6-dienylmalonates. The reaction of ABCDs with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) catalyzed by Yb(OTf)3 also results in the opening of both cyclopropane rings. The reaction products are tetrahydropyridazine derivatives  (7,9-dioxo-1,6,8-triazabicyclo[4.3.0]non-3-en-2-ylmethyl)malonates  containing one more PTAD moiety in the malonyl group.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Donor–Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes

et al. 2020

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“…[12]). Subsequent treatment of 4a-4f with thiourea in acetonitrile, in the presence of sodium carbonate, yielded the respective 2-amino-6,6-diorganyl-6-sila-4,5,6,7-tetrahydrobenzo[d]thiazoles 5a-5f,w hich upon reaction with phenyl N-(2-chloro-4ethoxy-5-morpholinobenzoyl)carbamate (6)o rp henyl N-(2chloro-4-ethoxy-5-(1H-pyrazol-1-yl)benzoyl)carbamate (7)i nt oluenef inally afforded the target compounds 1a-1f and 2a-2f,r espectively.…”

Section: Synthesesmentioning

confidence: 99%

“…[2][3][4] In contrastt oG PR109A, there are only af ew reported agonists for GPR81, and there is still an eed to identify potent GPR81 agonists as pharmacological tools. [5][6][7][8] Ah igh-throughput screen identifieda na cylurea-based GPR81a gonistl ead series, with activities on the GPR109A receptor as well. Ad etailed structure-activity relationship (SAR) analysiso ft his lead series will be published separately.T oe xplore GPR81 pharmacology in vivo, selectivity is an important issue.…”

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confidence: 99%

Synthesis and Pharmacological Properties of Silicon‐Containing GPR81 and GPR109A Agonists

et al. 2015

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The GPR81 and GPR109A receptors mediate antilipolytic effects and are potential drug targets for the treatment of metabolic disorders such as dyslipidemia and type 2 diabetes. There is still a need to identify potent GPR81 agonists as pharmacological tools. A high-throughput screen identified an acylurea-based GPR81 agonist lead series, with activities at the GPR109A receptor as well. To expand the chemical scope and to explore the pharmacological and pharmacokinetic consequences, a series of structurally related organosilicon compounds with a 6-sila-4,5,6,7-tetrahydrobenzo[d]thiazole skeleton was synthesized and studied for their physicochemical properties [octanol/water distribution coefficient (pH 7.4), solubility in HBSS buffer (pH 7.4)], agonistic potency at rat GPR81 and GPR109A receptors, and intrinsic clearance in human liver microsomes and rat hepatocytes. The straightforward synthesis of these organosilicon compounds offered a valuable expansion of the chemical scope in the above-mentioned GPR81 agonist lead series, provided potency and efficacy SAR, and yielded compounds with sub-micromolar GPR81 potency. This work supports the value of including silicon chemistry into the toolbox of medicinal chemistry.

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“…They all are G protein-coupled receptors and are predominantly expressed in adipocytes, where they mediate antilipolytic effects through coupling to the G αi protein pathway. 5,6 Activation of the HCA 2 receptor can have therapeutic benefits, such as an anti-dyslipidemic effect, 7 neuroprotective effect, 8, 9 and anti-inflammatory effect. [10][11][12] For the past 50 years nicotinic acid has been used to treat patients who suffer from dyslipidemia, cardiovascular disease and progression of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists

Veldhoven

Liu

Thee

et al. 2015

Bioorganic & Medicinal Chemistry

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Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists

Cited by 10 publications

References 33 publications

Donor–Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes

Donor–Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes

Synthesis and Pharmacological Properties of Silicon‐Containing GPR81 and GPR109A Agonists

Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists

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