Process Development and Scale-up of <b>AG035029</b>

Sáenz, James; Mitchell, Mark B.; Bahmanyar, Sami; Stanković, Nebojša; Perry, M Thrift; Craig-Woods, Bridgette; Kline, Billie J.; Yu, Shu; Albizati, Kim F.

doi:10.1021/op0601621

Cited by 17 publications

(16 citation statements)

References 7 publications

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“…The alkylation of methyl 1 H -indazole-3-carboxylate ( 12 ) proceeded regioselectively to favour the formation of 1-substituted 1 H -indazole intermediates as major products, entirely consistent with the known reactivity of indazoles towards nucleophilic substitution [ 56 – 58 ]. To quantify the regioselectivity of each alkylation method, the isolated yields of the regioisomeric products obtained following alkylation of 12 under each set of conditions for two representative bromoalkanes were determined are shown in Table 1 .…”

Section: Resultssupporting

confidence: 54%

The 2-alkyl-2H-indazole regioisomers of synthetic cannabinoids AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities

et al. 2016

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Indazole-derived synthetic cannabinoids (SCs) featuring an alkyl substituent at the 1-position and l-valinamide at the 3-carboxamide position (e.g., AB-CHMINACA) have been identified by forensic chemists around the world, and are associated with serious adverse health effects. Regioisomerism is possible for indazole SCs, with the 2-alkyl-2H-indazole regioisomer of AB-CHMINACA recently identified in SC products in Japan. It is unknown whether this regiosiomer represents a manufacturing impurity arising as a synthetic byproduct, or was intentionally synthesized as a cannabimimetic agent. This study reports the synthesis, analytical characterization, and pharmacological evaluation of commonly encountered indazole SCs AB-CHMINACA, AB-FUBINACA, AB-PINACA, 5F-AB-PINACA and their corresponding 2-alkyl-2H-indazole regioisomers. Both regioisomers of each SC were prepared from a common precursor, and the physical properties, 1H and 13C nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry, and ultraviolet–visible spectroscopy of all SC compounds are described. Additionally, AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA were found to act as high potency agonists at CB1 (EC50 = 2.1–11.6 nM) and CB2 (EC50 = 5.6–21.1 nM) receptors in fluorometric assays, while the corresponding 2-alkyl-2H-indazole regioisomers demonstrated low potency (micromolar) agonist activities at both receptors. Taken together, these data suggest that 2-alkyl-2H-indazole regioisomers of AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are likely to be encountered by forensic chemists and toxicologists as the result of improper purification during the clandestine synthesis of 1-alkyl-1H-indazole regioisomers, and can be distinguished by differences in gas chromatography–mass spectrometry fragmentation pattern.Electronic supplementary materialThe online version of this article (doi:10.1007/s11419-016-0316-y) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 54%

The 2-alkyl-2H-indazole regioisomers of synthetic cannabinoids AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities

et al. 2016

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“…Drug doses were chosen for near-maximal insulin-sensitizing effect without nonspecific effects (approximate EC 90 doses) (27,50,54). AG-035029 (22,38) is an experimental PPAR␥-selective ligand obtained from Pfizer, Inc., La Jolla, CA (see also DISCUSSION). Lean control (LC) rats were all fed normal chow.…”

Section: Methodsmentioning

confidence: 99%

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Hsiao

Chapman

Ofrecio³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Platinum on carbon (Pt/C) is oen used for reduction of nitro to amine in a mild condition without affecting other adjacent groups. [28][29][30] Here, Pt/C was also successfully employed to reduce the nitro group under ambient condition using an H 2 balloon without loss of the benzyl group to produce 12 in excellent yield (Scheme 1, vii).…”

Section: Resultsmentioning

confidence: 99%

Macrocyclic pentamers functionalised around their periphery as potential building blocks

2019

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Process Development and Scale-up of AG035029

Cited by 17 publications

References 7 publications

The 2-alkyl-2H-indazole regioisomers of synthetic cannabinoids AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities

The 2-alkyl-2H-indazole regioisomers of synthetic cannabinoids AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Macrocyclic pentamers functionalised around their periphery as potential building blocks

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