共查询到20条相似文献,搜索用时 15 毫秒
1.
Sun W Liu K Ryu H Kang DW Kim YS Kim MS Cho Y Bhondwe RS Thorat SA Kim HS Pearce LV Pavlyukovets VA Tran R Morgan MA Lazar J Ryder CB Toth A Blumberg PM Lee J 《Bioorganic & medicinal chemistry》2012,20(3):1310-1318
On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure-activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with K(i)=21.5nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with K(i(ant))=8.0nM comparable to 3. 相似文献
2.
Sunho Lee Changhoon Kim Jihyae Ann Shivaji A. Thorat Eunhye Kim Jongmi Park Sun Choi Peter M. Blumberg Robert Frank-Foltyn Gregor Bahrenberg Hannelore Stockhausen Thomas Christoph Jeewoo Lee 《Bioorganic & medicinal chemistry letters》2017,27(18):4383-4388
A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(16):4044-4047
A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(16):4039-4043
A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode. 相似文献
5.
Bhondwe RS Kang DW Kim MS Kim HS Park SG Son K Choi S Kuhs KA Pavlyukovets VA Pearce LV Blumberg PM Lee J 《Bioorganic & medicinal chemistry letters》2012,22(11):3656-3660
The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino)benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor. 相似文献
6.
Shao B Huang J Sun Q Valenzano KJ Schmid L Nolan S 《Bioorganic & medicinal chemistry letters》2005,15(3):719-723
A series of 4-(2-pyridyl)piperazine-1-benzimidazole analogues based on compound 1 was synthesized and evaluated for TRPV1 antagonist activity in capsaicin-induced (CAP) and pH5.5-induced (pH) FLIPR assays in a human TRPV1-expressing HEK293 cell line. Potent TRPV1 antagonists were identified through SAR studies. From these studies, several antagonists were found, with IC(50) values ranging from 32 nM to approximately 5000 nM. Among these, 11 [IC(50)=90 nM (CAP) and 104 nM (pH)] was further evaluated and found to be orally available in rats (F%=19.7). 相似文献
7.
Lee J Kang SU Kil MJ Shin M Lim JO Choi HK Jin MK Kim SY Kim SE Lee YS Min KH Kim YH Ha HJ Tran R Welter JD Wang Y Szabo T Pearce LV Lundberg DJ Toth A Pavlyukovets VA Morgan MA Blumberg PM 《Bioorganic & medicinal chemistry letters》2005,15(18):4136-4142
The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist. 相似文献
8.
Lee J Jin MK Kang SU Kim SY Lee J Shin M Hwang J Cho S Choi YS Choi HK Kim SE Suh YG Lee YS Kim YH Ha HJ Toth A Pearce LV Tran R Szabo T Welter JD Lundberg DJ Wang Y Lazar J Pavlyukovets VA Morgan MA Blumberg PM 《Bioorganic & medicinal chemistry letters》2005,15(18):4143-4150
The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed. 相似文献
9.
Tae-Hwan Ha HyungChul Ryu Sung-Eun Kim Ho Shin Kim Jihyae Ann Phuong-Thao Tran Van-Hai Hoang Karam Son Minghua Cui Sun Choi Peter M. Blumberg Robert Frank Gregor Bahrenberg Klaus Schiene Thomas Christoph Sven Frormann Jeewoo Lee 《Bioorganic & medicinal chemistry》2013,21(21):6657-6664
A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode. 相似文献
10.
Chung JU Kim SY Lim JO Choi HK Kang SU Yoon HS Ryu H Kang DW Lee J Kang B Choi S Toth A Pearce LV Pavlyukovets VA Lundberg DJ Blumberg PM 《Bioorganic & medicinal chemistry》2007,15(18):6043-6053
A series of alpha-substituted N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. alpha-Methyl substituted analogues showed potent and stereospecific antagonism to the action of capsaicin on rat TRPV1 heterologously expressed in Chinese hamster ovary cells. In particular, compounds 14 and 18, which possess the R-configuration, exhibited excellent potencies (respectively, K(i)=41 and 39.2 nM and K(i(ant))=4.5 and 37 nM). 相似文献
11.
Changhoon Kim Jihyae Ann Sunho Lee Wei Sun Peter M. Blumberg Robert Frank-Foltyn Gregor Bahrenberg Hannelore Stockhausen Thomas Christoph Jeewoo Lee 《Bioorganic & medicinal chemistry letters》2018,28(14):2539-2542
A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin. Further studies demonstrated that antagonist 6 blocked the hypothermic effect of capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising analgesic activity in the formalin animal model. 相似文献
12.
Gore VK Ma VV Tamir R Gavva NR Treanor JJ Norman MH 《Bioorganic & medicinal chemistry letters》2007,17(21):5825-5830
A novel series of 4,5-biarylimidazoles as TRPV1 antagonists were designed based on the previously reported 4,6-disubstituted benzimidazole series. The analogs were evaluated for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. These studies led to the identification of a highly potent and orally bioavailable TRPV1 antagonist, imidazole 33. 相似文献
13.
Wiesner J Mitsch A Wissner P Krämer O Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2002,12(19):2681-2683
In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties. 相似文献
14.
《Bioorganic & medicinal chemistry》2016,24(6):1231-1240
A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S. 相似文献
15.
Wiesner J Fucik K Kettler K Sakowski J Ortmann R Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2003,13(9):1539-1541
We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino group into the alpha-position of the arylpropionyl residue resulted in decreased activity. 相似文献
16.
Wiesner J Kettler K Sakowski J Ortmann R Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2003,13(3):361-363
We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl substituted derivative displayed an IC(50) of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2. 相似文献
17.
Wiesner J Kettler K Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2002,12(4):543-545
We have described 5-(4-propoxycinnamoylamino)-2-(4-tolylacetylamino)benzophenone 6e as a novel lead for anti-malarial agents. Anti-malarial activity of these 5-(4-propoxycinnamoylamino)benzophenones proved to be quite sensitive against variations of the acyl substituent at the 2-amino group. Best activity was obtained with phenylacetic acid moieties carrying small substituents in the para-position. From the para-substituents evaluated, the trifluoromethyl group yielded the most active compound (6j) in this series (IC50=120 nM). Deviations from the phenylacetic acid substructure, shifting the substituent into the ortho-position or bulkier para-substituents resulted in a significant reduction in anti-malarial activity. 相似文献
18.
Roh EJ Keller JM Olah Z Iadarola MJ Jacobson KA 《Bioorganic & medicinal chemistry》2008,16(20):9349-9358
Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel 'enhancers' of TRPV1 activity by examining changes in capsaicin-induced elevations in (45)Ca(2+)-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on (45)Ca(2+)-uptake by typically 2- to 3-fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca(2+), as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion. 相似文献
19.
Muraglia E Ontoria JM Branca D Dessole G Bresciani A Fonsi M Giuliano C Llauger Bufi L Monteagudo E Palumbi MC Torrisi C Rowley M Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2011,21(18):5283-5288
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies. 相似文献
20.
Finke PE Oates B Mills SG MacCoss M Malkowitz L Springer MS Gould SL DeMartino JA Carella A Carver G Holmes K Danzeisen R Hazuda D Kessler J Lineberger J Miller M Schleif WA Emini EA 《Bioorganic & medicinal chemistry letters》2001,11(18):2475-2479
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists. 相似文献