共查询到20条相似文献,搜索用时 31 毫秒
1.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Akifumi Morimoto Ken-ichi Kasahara Shigeki Ohashi Hiroko Suzuki Takahiko Hayashi Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(24):6569-6576
We describe a medicinal chemistry approach for generating a series of 2-(1H-pyrazol-1-yl)thiazoles as EP1 receptor antagonists. To improve the physicochemical properties of compound 1, we investigated its structure–activity relationships (SAR). Optimization of this lead compound provided small compound 25 which exhibited the best EP1 receptor antagonist activity and a good SAR profile. 相似文献
2.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Akifumi Morimoto Ken-ichi Kasahara Shigeki Ohashi Hiroko Suzuki Takahiko Hayashi Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(22):6064-6067
We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics. 相似文献
3.
Anja B. Scheiff Swapnil G. Yerande Ali El-Tayeb Wenjin Li Gajanan S. Inamdar Kamala K. Vasu Vasudevan Sudarsanam Christa E. Müller 《Bioorganic & medicinal chemistry》2010,18(6):2195-2203
A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A1-selective antagonists. Acylation of the 2-amino group was found to be crucial for high A1 affinity. The best compound of the present series was 2-benzoylamino-5-p-methylbenzoyl-4-phenylthiazole (16m) showing a Ki value of 4.83 nM at rat and 57.4 nM at human A1 receptors combined with high selectivity versus the other AdoR subtypes. The compound behaved as an antagonist in GTP shift assays at A1 receptors. Compound 16m may serve as a new lead structure for the development of second-generation non-xanthine-derived A1 antagonists which have potential as novel drugs. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(11):2481-2485
Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3. 相似文献
5.
Gabriele Murineddu Francesco Deligia Giulio Ragusa Laura García-Toscano María Gómez-Cañas Battistina Asproni Valentina Satta Elena Cichero Ruth Pazos Paola Fossa Giovanni Loriga Javier Fernández-Ruiz Gerard A. Pinna 《Bioorganic & medicinal chemistry》2018,26(1):295-307
A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6?nM for CB1 receptors and >40?μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2?nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist. 相似文献
6.
Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b, comprising a p-Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC50 = 0.084 μM) and protons (IC50 = 0.313 μM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs. 相似文献
7.
Panayiotis A. Procopiou Christopher Browning Paul M. Gore Sean M. Lynn Stephen A. Richards Robert J. Slack Steven L. Sollis 《Bioorganic & medicinal chemistry》2012,20(20):6097-6108
5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β?ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H1 receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pKi) for the human H1 receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA2) and a corresponding increase in lipophilicity. Introduction of a β-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H1 pA2 slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H3 receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H1 H3 receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1. 相似文献
8.
High throughput screening of the Roche compound library identified benzanilides such as 1 and 2 as antagonists of TAAR1. Optimisation of this hit series led to the first selective TAAR1 antagonist (N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide EPPTB (RO5212773, 9f) having IC50 of 28 nM at mouse TAAR1. 相似文献
9.
Tammy C. Wang Jennifer X. Qiao Charles G. Clark Ji Jua Laura A. Price Qimin Wu Ming Chang Joanna Zheng Christine S. Huang Gerry Everlof William A. Schumacher Pancras C. Wong Dietmar A. Seiffert Anne B. Stewart Jeffrey S. Bostwick Earl J. Crain Carol A. Watson Robert Rehfuss Patrick Y.S. Lam 《Bioorganic & medicinal chemistry letters》2013,23(11):3239-3243
10.
Alec D. Lebsack Bryan J. Branstetter Michael D. Hack Wei Xiao Matthew L. Peterson Nadia Nasser Michael P. Maher Hong Ao Anindya Bhattacharya Mena Kansagara Brian P. Scott Lin Luo Raymond Rynberg Michele Rizzolio Sandra R. Chaplan Alan D. Wickenden J. Guy Breitenbucher 《Bioorganic & medicinal chemistry letters》2009,19(1):40-46
We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure–activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED50 = 0.5 mg/kg in rats. 相似文献
11.
Adenosine A1 and A2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A1 and A2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A1 receptor with Ki values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A2A receptor. These substitution patterns led to enhanced adenosine A1 and A2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A1 and A2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. 相似文献
12.
《Bioorganic & medicinal chemistry》2016,24(11):2486-2503
Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q–u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats. 相似文献
13.
Andrew M.K. Pennell James B. Aggen Subhabrata Sen Wei Chen Yuan Xu Edward Sullivan Lianfa Li Kevin Greenman Trevor Charvat Derek Hansen Daniel J. Dairaghi J.J. Kim Wright Penglie Zhang 《Bioorganic & medicinal chemistry letters》2013,23(5):1228-1231
A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC50 = 4 nM using [125I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species. 相似文献
14.
Miguel Guerrero Mariangela Urbano Marie-Therese Schaeffer Steven Brown Hugh Rosen Edward Roberts 《Bioorganic & medicinal chemistry letters》2013,23(3):614-619
In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure–activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC50, and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function. 相似文献
15.
Romano Silvestri Alessia Ligresti Giuseppe La Regina Francesco Piscitelli Valerio Gatti Antonella Brizzi Serena Pasquini Antonio Lavecchia Marco Allarà Noemi Fantini Mauro Antonio Maria Carai Ettore Novellino Giancarlo Colombo Vincenzo Di Marzo Federico Corelli 《Bioorganic & medicinal chemistry》2009,17(15):5549-5564
New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB1 receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB1 receptor, with Ki concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB1 selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB1 binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB1 selective compounds 4 and 52 act as antagonists/inverse agonists. 相似文献
16.
Nafizal Hossain Svetlana Ivanova Jonas Bergare Tomas Eriksson 《Bioorganic & medicinal chemistry letters》2013,23(6):1883-1886
Conformationally constrained spirocycles (17–23) and (31–36) were synthesised. In vitro data revealed that these compounds are CCR1 antagonists with sub-nanomolar potency. In a functional assay 22, 23 and 36 inhibited CCR1 mediated chemotaxis with an IC50 value of 2, 2.6 and 68 nM, respectively. 相似文献
17.
Max Keller Melanie Kaske Tobias Holzammer Günther Bernhardt Armin Buschauer 《Bioorganic & medicinal chemistry》2013,21(21):6303-6322
The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a Kb value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. 相似文献
18.
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
19.
Jeffrey C. Kern Eugene Terefenko Eugene Trybulski Thomas J. Berrodin Jeffrey Cohen Richard C. Winneker Matthew R. Yudt Zhiming Zhang Yuan Zhu Puwen Zhang 《Bioorganic & medicinal chemistry letters》2010,20(16):4816-4818
Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic derivatives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alkaline phosphatase assay. Moderate to potent PR antagonists were achieved with these scaffolds. Several compounds (e.g., 15 and 20) demonstrated low nanomolar PR antagonist potency and good selectivity versus other steroid receptors. 相似文献
20.
Takuto Kojima Michiyo Mochizuki Takafumi Takai Yasutaka Hoashi Sachie Morimoto Masaki Seto Minoru Nakamura Katsumi Kobayashi Yuu Sako Maiko Tanaka Naoyuki Kanzaki Yohei Kosugi Takahiko Yano Kazuyoshi Aso 《Bioorganic & medicinal chemistry》2018,26(9):2229-2250
A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a–e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a–e showed CRF1 receptor binding activity with IC50 values of less than 400?nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50?=?7.1?nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R, which exhibited potent CRF1 receptor binding activity (IC50?=?58?nM) with good oral bioavailability (F?=?68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10?mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10?mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies. 相似文献