共查询到20条相似文献,搜索用时 9 毫秒
1.
《Bioorganic & medicinal chemistry letters》2014,24(15):3285-3290
A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety. 相似文献
2.
Baxter A Cooper A Kinchin E Moakes K Unitt J Wallace A 《Bioorganic & medicinal chemistry letters》2006,16(4):960-963
A Hit-to-Lead optimisation programme was carried out on a high throughput screening hit, the thiazolopyrimidine 1, resulting in the discovery of the potent, orally bioavailable CXCR2 antagonist 29. 相似文献
3.
Hit-to-lead studies: the discovery of potent,orally bioavailable triazolethiol CXCR2 receptor antagonists 总被引:2,自引:0,他引:2
Baxter A Bennion C Bent J Boden K Brough S Cooper A Kinchin E Kindon N McInally T Mortimore M Roberts B Unitt J 《Bioorganic & medicinal chemistry letters》2003,13(16):2625-2628
A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45. 相似文献
4.
Jin Q Nie H McCleland BW Widdowson KL Palovich MR Elliott JD Goodman RM Burman M Sarau HM Ward KW Nord M Orr BM Gorycki PD Busch-Petersen J 《Bioorganic & medicinal chemistry letters》2004,14(17):4375-4378
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation. 相似文献
5.
Chao J Taveras AG Chao J Aki C Dwyer M Yu Y Purakkattle B Rindgen D Jakway J Hipkin W Fosetta J Fan X Lundell D Fine J Minnicozzi M Phillips J Merritt JR 《Bioorganic & medicinal chemistry letters》2007,17(13):3778-3783
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog. 相似文献
6.
Ian M. Bell Rodney A. Bednar Halea A. Corcoran John F. Fay Steven N. Gallicchio Victor K. Johnston James C. Hershey Cynthia M. Miller-Stein Eric L. Moore Scott D. Mosser Shane A. Roller Christopher A. Salvatore Cory R. Theberge Bradley K. Wong C. Blair Zartman Stefanie A. Kane Theresa M. Williams Samuel L. Graham Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2009,19(16):4740-4742
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species. 相似文献
7.
中性粒细胞属非特异性免疫细胞,其表面可表达CXCR1和CXCR2.IL-8是其共同配体,它们彼此结合激活后续级联信号传导,产生一系列生物学效应,在介导炎症反应、促进血管新生、维持中性粒细胞稳态等起重要作用.Reparixin是非竞争变构的CXCR1和CXCR2阻滞剂,可抑制中性粒细胞过度趋化、迁移介导的炎症反应. 相似文献
8.
The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine 总被引:2,自引:0,他引:2
Lin P Chang L Devita RJ Young JR Eid R Tong X Zheng S Ball RG Tsou NN Chicchi GG Kurtz MM Tsao KL Wheeldon A Carlson EJ Eng W Burns HD Hargreaves RJ Mills SG 《Bioorganic & medicinal chemistry letters》2007,17(18):5191-5198
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml. 相似文献
9.
Lin LS Kopka IE Mumford RA Magriotis PA Lanza T Durette PL Kamenecka T Young DN de Laszlo SE McCauley E Riper GV Kidambi U Egger LA Tong X Lyons K Vincent S Stearns R Colletti A Teffera Y Fenyk-Melody J Schmidt JA MacCoss M Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):611-614
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. 相似文献
10.
Miller WH Manley PJ Cousins RD Erhard KF Heerding DA Kwon C Ross ST Samanen JM Takata DT Uzinskas IN Yuan CC Haltiwanger RC Gress CJ Lark MW Hwang SM James IE Rieman DJ Willette RN Yue TL Azzarano LM Salyers KL Smith BR Ward KW Johanson KO Huffman WF 《Bioorganic & medicinal chemistry letters》2003,13(8):1483-1486
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123. 相似文献
11.
Fujimoto T Kunitomo J Tomata Y Nishiyama K Nakashima M Hirozane M Yoshikubo S Hirai K Marui S 《Bioorganic & medicinal chemistry letters》2011,21(21):6414-6416
During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2019,29(20):126668
Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(7):1843-1845
We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment. 相似文献
14.
Bell IM Bednar RA Fay JF Gallicchio SN Hochman JH McMasters DR Miller-Stein C Moore EL Mosser SD Pudvah NT Quigley AG Salvatore CA Stump CA Theberge CR Wong BK Zartman CB Zhang XF Kane SA Graham SL Vacca JP Williams TM 《Bioorganic & medicinal chemistry letters》2006,16(24):6165-6169
A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species. 相似文献
15.
《Bioorganic & medicinal chemistry letters》2014,24(23):5493-5496
2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. 相似文献
16.
Watson RJ Allen DR Birch HL Chapman GA Hannah DR Knight RL Meissner JW Owen DA Thomas EJ 《Bioorganic & medicinal chemistry letters》2007,17(24):6806-6810
Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4 h. 相似文献
17.
Michael P. DeNinno Melissa Andrews Andrew S. Bell Yue Chen Cynthia Eller-Zarbo Nan Eshelby John B. Etienne Dianna E. Moore Michael J. Palmer Michael S. Visser Li J. Yu William J. Zavadoski E. Michael Gibbs 《Bioorganic & medicinal chemistry letters》2009,19(9):2537-2541
Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition. 相似文献
18.
Craig A. Stump Ian M. Bell Rodney A. Bednar Joseph G. Bruno John F. Fay Steven N. Gallicchio Victor K. Johnston Eric L. Moore Scott D. Mosser Amy G. Quigley Christopher A. Salvatore Cory R. Theberge C. Blair Zartman Xu-Fang Zhang Stefanie A. Kane Samuel L. Graham Joseph P. Vacca Theresa M. Williams 《Bioorganic & medicinal chemistry letters》2009,19(1):214-217
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP Ki = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus. 相似文献
19.
Matthew A.J. Duncton Eugene L. Piatnitski Chekler Reeti Katoch-Rouse Dan Sherman Wai C. Wong Leon M. Smith Joel K. Kawakami Alexander S. Kiselyov Daniel L. Milligan Chris Balagtas Yaron R. Hadari Ying Wang Sheetal N. Patel Robin L. Rolster James R. Tonra David Surguladze Stan Mitelman Paul Kussie Peter Bohlen Jacqueline F. Doody 《Bioorganic & medicinal chemistry》2009,17(2):731-740
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice. 相似文献
20.
Morales-Ramos ÁI Li YH Hilfiker M Mecom JS Eidam P Shi D Tseng PS Brooks C Zhang D Wang N Jaworski JP Morrow D Fries H Edwards R Jin J 《Bioorganic & medicinal chemistry letters》2011,21(10):2806-2811
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP3 receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed. 相似文献