143937-74-0Relevant articles and documents
High affinity antagonists of the vanilloid receptor
Wang, Yun,Szabo, Tamas,Welter, Jacqueline D.,Toth, Attila,Tran, Richard,Lee, Jiyoun,Kang, Sang Uk,Suh, Young-Ger,Blumberg, Peter M.,Lee, Jeewoo
, p. 947 - 956 (2002)
The vanilloid receptor VR1 has attracted great interest as a sensory transducer for capsaicin, protons, and heat, and as a therapeutic target. Here we characterize two novel VR1 antagonists, KJM429 [N-(4-tert-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea] and JYL1421 [N-(4-tertbutylbenzyl)-N′-[3-fluoro-4-(methylsulfonylamino)benzyl] -thiourea], with enhanced activity compared with capsazepine on rat VR1 expressed in Chinese hamster ovary (CHO) cells. JYL1421, the more potent of the two novel antagonists, inhibited [3H]resiniferatoxin binding to rVR1 with an affinity of 53.5 ± 6.5 nM and antagonized capsaicin-induced calcium uptake with an EC50 of 9.2 ± 1.6 nM, reflecting 25- and 60-fold greater potencies than capsazepine. Both JYL1421 and KJM429 antagonized RTX as well as capsaicin and their mechanism was competitive. The responses to JYL1421 and KJM429 differed for calcium uptake by rVR1 induced by heat or pH. JYL1421 antagonized the response to both pH 6.0 and 5.5, whereas KJM429 antagonized at pH 6.0 but was an agonist at lower pH (5.5). For heat, JYL1421 fully antagonized and KJM429 partially antagonized. Capsazepine showed only weak antagonism for both pH and heat. Responses of rVR1 to different activators could thus be differentially affected by different ligands. In cultured dorsal root ganglion neurons, JYL1421 and KJM429 likewise behaved as antagonists for capsaicin, confirming that the antagonism is not limited to heterologous expression systems. Finally, JYL1421 and KJM429 had little or no effect on ATP-induced calcium uptake in CHO cells lacking rVR1, unlike capsazepine. We conclude that JYL1421 is a competitive antagonist of rVR1, blocking response to all three of the agonists (capsaicin, heat, and protons) with enhanced potency relative to capsazepine.
Synthesis and Reactivity of 18F-Labeled α,α-Difluoro-α-(aryloxy)acetic Acids
Khotavivattana, Tanatorn,Calderwood, Samuel,Verhoog, Stefan,Pfeifer, Lukas,Preshlock, Sean,Vasdev, Neil,Collier, Thomas L.,Gouverneur, Véronique
supporting information, p. 568 - 571 (2017/02/10)
In this work, we describe the 18F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-18F-fluorination functionalization. Protodecarboxylation offers a new entry to 18F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative 18F-labeled TRPV1 inhibitors and TRPV1 antagonists.
COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND USES THEREOF IN MEDICINE
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Paragraph 00179, (2016/01/25)
Provided herein are compounds of Formula (I), or a stereoisomer, a geometric isomer, an enantiomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which are used in the treatment of HCV
Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands
Kim, Myeong Seop,Ki, Yooran,Ahn, Song Yeon,Yoon, Suyoung,Kim, Sung-Eun,Park, Hyeung-Geun,Sun, Wei,Son, Karam,Cui, Minghua,Choi, Sun,Pearce, Larry V.,Esch, Timothy E.,Deandrea-Lazarus, Ian A.,Blumberg, Peter M.,Lee, Jeewoo
, p. 382 - 385 (2014/01/17)
The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R.
Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands
Kim, Myeong Seop,Ki, Yooran,Ahn, Song Yeon,Yoon, Suyoung,Kim, Sung-Eun,Park, Hyeung-Geun,Lee, Jeewoo,Sun, Wei,Son, Karam,Cui, Minghua,Choi, Sun,Pearce, Larry V.,Esch, Timothy E.,DeAndrea-Lazarus, Ian A.,Blumberg, Peter M.
, p. 382 - 385 (2015/03/18)
The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R.
Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands
Kim, Myeong Seop,Ki, Yooran,Ahn, Song Yeon,Yoon, Suyoung,Kim, Sung-Eun,Park, Hyeung-Geun,Sun, Wei,Son, Karam,Cui, Minghua,Choi, Sun,Pearce, Larry V.,Esch, Timothy E.,Deandrea-Lazarus, Ian A.,Blumberg, Peter M.,Lee, Jeewoo
, p. 382 - 385 (2015/08/19)
The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R.
TRPV1 ANTAGONISTS
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Paragraph 0199, (2014/02/15)
Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, or combinations thereof, wherein X1, L, Rx, Ry, Rz, R1, R2, A, m, n, p, q, and r are defined in
Convergent asymmetric synthesis of two complex TRPV1 antagonists
Butcher, Kenneth J.,Denton, Steven M.,Field, Stuart E.,Gillmore, Adam T.,Harbottle, Gareth W.,Howard, Roger M.,Laity, Daniel A.,Ngono, Christian J.,Pibworth, Benjamin A.
scheme or table, p. 1192 - 1200 (2011/12/16)
The convergent scale-up synthesis of two complex TRPV1 antagonists to support exploratory toxicology studies is described. Both compounds contain three chiral centers introduced by asymmetric synthesis with chiral control being critical for the success of the project. Preparation of the key cyclopropyl intermediate utilised an asymmetric cyclopropanation using thermally unstable ethyl diazoacetate. Ellman's auxiliary was used to synthesize the chiral α-methyl benzylamine fragments. This paper highlights some of the key synthetic challenges, processing issues, and safety aspects from the scale-up of this chemistry.
Heterocyclic antiviral compounds
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, (2010/02/17)
Compounds having the formula I wherein R1, R2, R3, R4a, R4b, R4c, R5, R6, R9 and n are as defined herein are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.
Design, synthesis, and biological evaluation of novel diarylalkyl amides as TRPV1 antagonists
Li, Fu-Nan,Kim, Nam-Jung,Paek, Seung-Mann,Kwon, Do-Yeon,Min, Kyung Hoon,Jeong, Yeon-Su,Kim, Sun-Young,Park, Young-Ho,Kim, Hee-Doo,Park, Hyeung-Geun,Suh, Young-Ger
experimental part, p. 3557 - 3567 (2009/09/27)
We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent 45Ca2+ uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antagonist with IC50 of 57 nM. The synthesis and structure-activity relationship of the diarylalkyl amides are also described.
