共查询到20条相似文献,搜索用时 15 毫秒
1.
Li X McCoy KA Murray WV Jolliffe L Pulito V 《Bioorganic & medicinal chemistry letters》2000,10(20):2375-2377
A novel series of aryl piperazine substituted heterocycles has been synthesized and identified as antagonists of the alpha1a-adrenergic receptor (alpha1a-AR), which has been implicated in benign prostatic hyperplasia (BPH). These compounds selectively inhibit binding to the alpha1a-AR with K(i)s as low as 2.1 nM. 相似文献
2.
Brown MF Avery M Brissette WH Chang JH Colizza K Conklyn M DiRico AP Gladue RP Kath JC Krueger SS Lira PD Lillie BM Lundquist GD Mairs EN McElroy EB McGlynn MA Paradis TJ Poss CS Rossulek MI Shepard RM Sims J Strelevitz TJ Truesdell S Tylaska LA Yoon K Zheng D 《Bioorganic & medicinal chemistry letters》2004,14(9):2175-2179
The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described. 相似文献
3.
Kim D Wang L Hale JJ Lynch CL Budhu RJ Maccoss M Mills SG Malkowitz L Gould SL DeMartino JA Springer MS Hazuda D Miller M Kessler J Hrin RC Carver G Carella A Henry K Lineberger J Schleif WA Emini EA 《Bioorganic & medicinal chemistry letters》2005,15(8):2129-2134
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity. 相似文献
4.
Fox BM Natero R Richard K Connors R Roveto PM Beckmann H Haller K Golde J Xiao SH Kayser F 《Bioorganic & medicinal chemistry letters》2011,21(8):2460-2467
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition. 相似文献
5.
Chaozhong Cai Fu-An Kang Cuifen Hou John C. O’Neill Evan Opas Sandra McKenney Dana Johnson Zhihua Sui 《Bioorganic & medicinal chemistry letters》2013,23(1):351-354
Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed. 相似文献
6.
Hale JJ Budhu RJ Mills SG MacCoss M Malkowitz L Siciliano S Gould SL DeMartino JA Springer MS 《Bioorganic & medicinal chemistry letters》2001,11(11):1437-1440
A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [(125)I]-MIP-1alpha from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine. 相似文献
7.
Willoughby CA Rosauer KG Hale JJ Budhu RJ Mills SG Chapman KT MacCoss M Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Cascieri MA Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller M Emini EA 《Bioorganic & medicinal chemistry letters》2003,13(3):427-431
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1. 相似文献
8.
Lynch CL Willoughby CA Hale JJ Holson EJ Budhu RJ Gentry AL Rosauer KG Caldwell CG Chen P Mills SG MacCoss M Berk S Chen L Chapman KT Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Cascieri MA Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller M Emini EA 《Bioorganic & medicinal chemistry letters》2003,13(1):119-123
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics. 相似文献
9.
Revesz L Bollbuck B Buhl T Eder J Esser R Feifel R Heng R Hiestand P Jachez-Demange B Loetscher P Sparrer H Schlapbach A Waelchli R 《Bioorganic & medicinal chemistry letters》2005,15(23):5160-5164
Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis. 相似文献
10.
11.
Christian Harcken Christopher Sarko Can Mao John Lord Brian Raudenbush Hossein Razavi Pingrong Liu Alan Swinamer Darren Disalvo Thomas Lee Siqi Lin Alison Kukulka Heather Grbic Mita Patel Monica Patel Kim Fletcher David Joseph Della White David S. Thomson 《Bioorganic & medicinal chemistry letters》2019,29(3):435-440
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties. 相似文献
12.
Khatuya H Hutchings RH Kuo GH Pulito VL Jolliffe LK Li X Murray WV 《Bioorganic & medicinal chemistry letters》2002,12(17):2443-2446
Antagonists of the alpha(1)-adrenergic receptors (alpha(1)-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective alpha(1a)-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range. 相似文献
13.
Jin J Wang Y Wang F Kerns JK Vinader VM Hancock AP Lindon MJ Stevenson GI Morrow DM Rao P Nguyen C Barrett VJ Browning C Hartmann G Andrew DP Sarau HM Foley JJ Jurewicz AJ Fornwald JA Harker AJ Moore ML Rivero RA Belmonte KE Connor HE 《Bioorganic & medicinal chemistry letters》2007,17(6):1722-1725
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. 相似文献
14.
Leslie CP Di Fabio R Bonetti F Borriello M Braggio S Dal Forno G Donati D Falchi A Ghirlanda D Giovannini R Pavone F Pecunioso A Pentassuglia G Pizzi DA Rumboldt G Stasi L 《Bioorganic & medicinal chemistry letters》2007,17(4):1043-1046
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability. 相似文献
15.
Hale JJ Budhu RJ Mills SG MacCoss M Gould SL DeMartino JA Springer MS Siciliano SJ Malkowitz L Schleif WA Hazuda D Miller M Kessler J Danzeisen R Holmes K Lineberger J Carella A Carver G Emini EA 《Bioorganic & medicinal chemistry letters》2002,12(20):2997-3000
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity. 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.
Xia M Hou C Demong D Pollack S Pan M Brackley J Singer M Matheis M Cavender D Wachter M 《Bioorganic & medicinal chemistry letters》2008,18(12):3562-3564
The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC(50) values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs. 相似文献
18.
Aiko Nitta Yosuke Iura Hideki Inoue Ippei Sato Koichiro Morihira Hirokazu Kubota Tatsuaki Morokata Makoto Takeuchi Mitsuaki Ohta Shin-ichi Tsukamoto Takayuki Imaoka Toshiya Takahashi 《Bioorganic & medicinal chemistry letters》2012,22(22):6876-6881
Optimization starting with our lead compound 1 (IC50 = 4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC50 = 1.7 nM), a potent and orally active CCR3 antagonist. 相似文献
19.
Jonas Boström Roine I. Olsson Joakim Tholander Peter J. Greasley Erik Ryberg Henrik Nordberg Stephan Hjorth Leifeng Cheng 《Bioorganic & medicinal chemistry letters》2010,20(2):479-482
A novel class of cannabinoid-1 (CB1) receptor antagonists for the treatment of obesity is presented. The carboxamide linker in a set of 5,6-diaryl-pyrazine-2-amide derivatives was transformed into the corresponding thioamide, by using a one-pot synthesis. The structural series of thioamides not only showed retained CB1 potency (below 10 nM), but also showed improved solubility. In addition, the neutral antagonist 2c significantly reduced body weight in cafeteria diet obese mice. 相似文献
20.
Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1 总被引:2,自引:0,他引:2
Onuffer J McCarrick MA Dunning L Liang M Rosser M Wei GP Ng H Horuk R 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(4):1910-1916
A useful strategy for identifying ligand binding domains of G protein-coupled receptors has been the exploitation of species differences in antagonist potencies. We have used this approach for the CCR1 chemokine receptor with a novel series of antagonists, the 4-hydroxypiperidines, which were discovered by high throughput screening of human CCR1 and subsequently optimized. The structure-activity relationships for a number of different 4-hydroxypiperidine antagonists for human and mouse CCR1 were examined by receptor binding and functional assays. These compounds exhibit major differences in their rank order of potency for the human and mouse chemokine receptor CCR1. For example, the initial lead template, BX 510, which was a highly potent functional antagonist for human CCR1 (K(i) = 21 nM) was >400-fold less active on mouse CCR1 (K(i) = 9150 nM). However, increasing the length of the linker between the piperidine and dibenzothiepine groups by one methylene group generated a compound, BX 511, which was equipotent for both human and mouse CCR1. These and other analogs of the lead template BX 510, which have major differences in potency for human and mouse CCR1, are described, and a model for their interaction with human CCR1 is presented. 相似文献