Discovery of a Series of Indazole TRPA1 Antagonists

Pryde, David C.; Marron, Brian E.; West, Christopher W.; Reister, Steven; Amato, George; Yoger, Katrina; Antonio, Brett; Padilla, Karen; Cox, Peter; Turner, Jamie; Warmus, Joseph S.; Swain, Nigel A.; Omoto, Kiyoyuki; Mahoney, John H.; Gerlach, Aaron C.

doi:10.1021/acsmedchemlett.7b00140

Cited by 21 publications

(14 citation statements)

References 14 publications

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“…Pryde et al [ 98 ] reported a series of novel 1 H -indazole derivatives as transient receptor potential ankyrin-repeat 1 (TRPA1) antagonists. The authors investigated the derivatives’s physical properties and in vitro drug metabolism and pharmacokinetics (DMPK) profiles.…”

Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

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Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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“…[28] Benzazoles are under study as agentsa gainst tuberculosis [29] and some derivatives show antiheparanase activity, [30] which may potentially lead to anticancer treatments. In this work, we focus on indazole [31][32][33][34] and the subtle effect of aromatic bond length alternation. Determination of an accurate molecular structure would allow experimental observation of the effect.…”

Section: Introductionmentioning

confidence: 99%

Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

Uriarte

Reviriego

Calabrese

et al. 2019

Chemistry A European J

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Bond length alternation is a chemical phenomenon in benzene rings fused to other rings, which has been mainly predicted theoretically. Its physical origin is still not clear and has generated discussion. Here, by using a strategy that combines microwave spectroscopy, custom‐made synthesis and high‐level ab initio calculations, we demonstrate that this phenomenon is clearly observed in the prototype indazole molecule isolated in the gas phase. The 1H‐indazole conformer was detected by rotational spectroscopy, and its 17 isotopologues resulting from single and double heavy atom substitution (13C and 15N) were also unambiguously observed. Several experimental structures were determined and, in particular, the most useful semi‐experimental equilibrium structure (reSE), allowed determination of the heavy atom bond lengths to milli‐Ångstrom precision. The experimentally determined bond length alternation is estimated to correspond to 60:40 contributions from the two resonant forms of 1H‐indazole.

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“…Human-species ortholog chimeras of TRPA1 have proven useful to identify regions of the channel involved in species-dependent compound interactions. Previously, we demonstrated the opossum TRPA1 (oTRPA1) variant which shares 67% amino acid homology with hTRPA1 to be insensitive to carboxamide (Pfizer) and indazole (Novartis) TRPA1 inhibitors (24,25). Likewise, Compound 1 was found to be inactive vs. oTRPA1 ( Fig.…”

Section: Discovery Of a Novel And Selective Trpa1 Small Molecule Inhimentioning

confidence: 92%

TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype

Tseng

Pryde

Yoger³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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TRPA1, a member of the transient receptor potential channel (TRP) family, is genetically linked to pain in humans, and small molecule inhibitors are efficacious in preclinical animal models of inflammatory pain. These findings have driven significant interest in development of selective TRPA1 inhibitors as potential analgesics. The majority of TRPA1 inhibitors characterized to date have been reported to interact with the S5 transmembrane helices forming part of the pore region of the channel. However, the development of many of these inhibitors as clinical drug candidates has been prevented by high lipophilicity, low solubility, and poor pharmacokinetic profiles. Identification of alternate compound interacting sites on TRPA1 provides the opportunity to develop structurally distinct modulators with novel structure-activity relationships and more desirable physiochemical properties. In this paper, we have identified a previously undescribed potent and selective small molecule thiadiazole structural class of TRPA1 inhibitor. Using species ortholog chimeric and mutagenesis strategies, we narrowed down the site of interaction to ankyrinR #6 within the distal N-terminal region of TRPA1. To identify the individual amino acid residues involved, we generated a computational model of the ankyrinR domain. This model was used predictively to identify three critical amino acids in human TRPA1, G238, N249, and K270, which were confirmed by mutagenesis to account for compound activity. These findings establish a small molecule interaction region on TRPA1, expanding potential avenues for developing TRPA1 inhibitor analgesics and for probing the mechanism of channel gating.

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Discovery of a Series of Indazole TRPA1 Antagonists

Cited by 21 publications

References 14 publications

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype

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