共查询到20条相似文献,搜索用时 31 毫秒
1.
Richard A. Hartz Vivekananda M. Vrudhula Vijay T. Ahuja James E. Grace Nicholas J. Lodge Joanne J. Bronson John E. Macor 《Bioorganic & medicinal chemistry letters》2017,27(6):1360-1363
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2020,30(14):127258
PI-103 (7) is a potent dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, but its rapid in vivo metabolism hinders its further clinical development. To improve the bioavailability of PI-103, we designed and synthesized a PI-103 bioisostere, PI-103BE (9) in which the phenolic hydroxyl group of PI-103 was replaced by a boronate, a structural modification known to enhance bioavailability of molecules containing phenolic hydroxyl moieties. In cell culture, PI-103BE is partially converted to its corresponding boronic acid (10) and to a lesser extent the active ingredient, PI-103. This mixture contributes to the in vitro activity of 9 that shows reduced potency compared to the parent compound. When administered to mice by oral gavage, 9 displays a significantly improved pharmacokinetic profile compared to PI-103, which shows no oral bioavailability at the same dose. Drug exposure of 9 as measured by the area under curve (AUC) value is 88.2 ng/mL*h for 7 and 8879.9 ng/mL*h for 10. When given by intraperitoneal injection (IP), the prodrug afforded an AUC of 32.3 ng/mL*h for 7 and 400.9 ng/mL*h for 10, compared to 9.7 ng/mL*h from PI-103 injection. In plasma from both pharmacokinetic studies, 9 is fully converted to 10 and 7, with the boronic acid metabolite (10) displaying antiproliferative activities comparable to 9, but weaker than 7. The boronic bioisostere of PI-103 thus offers an improved bioavailability that could be translated to in vivo efficacy of PI-103. 相似文献
3.
Tsutomu Nagata Toshiharu Yoshino Noriyasu Haginoya Kenji Yoshikawa Masatoshi Nagamochi Syozo Kobayashi Satoshi Komoriya Aki Yokomizo Ryo Muto Mitsuhiro Yamaguchi Ken Osanai Makoto Suzuki Hideyuki Kanno 《Bioorganic & medicinal chemistry》2009,17(3):1193-1206
In the early 1990’s, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity. 相似文献
4.
Charles G. Clark Karen A. Rossi James R. Corte Tianan Fang Joanne M. Smallheer Indawati De Lucca David S. Nirschl Michael J. Orwat Donald J.P. Pinto Zilun Hu Yufeng Wang Wu Yang Yoon Jeon William R. Ewing Joseph E. Myers Steven Sheriff Zhen Lou Jeffrey M. Bozarth Patrick Y.S. Lam 《Bioorganic & medicinal chemistry letters》2019,29(19):126604
5.
Yu LiuZining Liu Xufeng CaoXin Liu Huili HeYushe Yang 《Bioorganic & medicinal chemistry letters》2011,21(16):4779-4783
To improve antifungal activities, water solubility and bioavailability, a series of novel analogues of itraconazole-containing pyridine rings were designed and synthesized. Their antifungal activities were evaluated in vitro against six clinically important fungi by measuring the minimal inhibitory concentrations (MICs). Most of the compounds showed more potent antifungal activities than that of itraconazole. In particular, the analogues 30d, 30c, 31c, and 36d exhibited much higher solubility and bioavailability than that of itraconazole. The bioavailability of 36d (42.2%) was five times higher than that of itraconazole (8%) and was negative for genetic toxicology in the Ames test. 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.
Yibin Xiang Bradford Hirth John L. Kane Junkai Liao Kevin D. Noson Christopher Yee Gary Asmussen Maria Fitzgerald Christine Klaus Michael Booker 《Bioorganic & medicinal chemistry letters》2010,20(15):4550-4554
Building on our initial work, we have identified additional novel inhibitors of sphingosine kinase-1 (SK1). These new analogs address the shortcomings found in our previously reported compounds. Inhibitors 51 and 54 demonstrated oral bioavailability in a rat PK study. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(10):2257-2272
Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system. 相似文献
9.
Earl Clarke Christopher I. Jarvis Maria B. Goncalves S. Barret Kalindjian David R. Adams Jane T. Brown Jason J. Shiers David M.A. Taddei Elodie Ravier Stephanie Barlow Iain Miller Vanessa Smith Alan D. Borthwick Jonathan P.T. Corcoran 《Bioorganic & medicinal chemistry》2018,26(4):798-814
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens. 相似文献
10.
Qingyi Meng Huibing Luo Yibin Liu Wei Li Wen Zhang Qizheng Yao 《Bioorganic & medicinal chemistry letters》2009,19(10):2808-2810
The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of SQ109 has been reported. Bioavailability of SQ109 after administration of prodrug 7a was 91.4% compared with 21.4% after oral administration of SQ109. After oral administration of compound 7a, the parent drug SQ109 exhibited preferential tissue distribution into lung and spleen, the target organs of tubercular infection and replication. 相似文献
11.
Kenneth J. Wilson Carl R. Illig Jinsheng Chen Mark J. Wall Shelley K. Ballentine Renee L. DesJarlais Yanmin Chen Carsten Schubert Robert Donatelli Ioanna Petrounia Carl S. Crysler Christopher J. Molloy Margery A. Chaikin Carl L. Manthey Mark R. Player Bruce E. Tomczuk Sanath K. Meegalla 《Bioorganic & medicinal chemistry letters》2010,20(13):3925-3929
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(24):5731-5737
This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration. 相似文献
13.
Christopher A. Hurley Wade S. Blair Richard J. Bull Christine Chang Peter H. Crackett Gauri Deshmukh Hazel J. Dyke Rina Fong Nico Ghilardi Paul Gibbons Peter R. Hewitt Adam Johnson Tony Johnson Jane R. Kenny Pawan Bir Kohli Janusz J. Kulagowski Marya Liimatta Patrick J. Lupardus Mark Zak 《Bioorganic & medicinal chemistry letters》2013,23(12):3592-3598
The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib). 相似文献
14.
Patrick Lacombe Renée Aspiotis Christopher Bayly Austin Chen Daniel Dubé Réjean Fortin Michel Gallant Hélène Juteau Suzanna Liu Dan McKay Patrick Roy Tom Wu 《Bioorganic & medicinal chemistry letters》2010,20(19):5822-5826
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC50 and good oral bioavailability in rats. 相似文献
15.
Yoshikazu Arai Yohei Kiyotsuka Kousei Shimada Kazunori Oyama Masanori Izumi 《Bioorganic & medicinal chemistry letters》2019,29(18):2613-2616
The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study. 相似文献
16.
17.
Alexander L. Ruchelman Hon-Wah Man Weihong Zhang Roger Chen Lori Capone Jian Kang Anastasia Parton Laura Corral Peter H. Schafer Darius Babusis Mehran F. Moghaddam Yang Tang Michael A. Shirley George W. Muller 《Bioorganic & medicinal chemistry letters》2013,23(1):360-365
A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat. 相似文献
18.
Masakazu Atobe Naomi Maekawara Masashi Kawanishi Hiroko Suzuki Eiichi Tanaka Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(7):2111-2116
A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability. 相似文献
19.
Jarkko Rautio Jukka Leppänen Marko Lehtonen Krista Laine Mikko Koskinen Jarmo Pystynen Jouko Savolainen Mikko Sairanen 《Bioorganic & medicinal chemistry letters》2010,20(8):2614-2616
Compound 1 is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats. 相似文献
20.
Masayuki Nakamura Hideki Kurihara Gentaroh Suzuki Morihiro Mitsuya Mitsuru Ohkubo Hisashi Ohta 《Bioorganic & medicinal chemistry letters》2010,20(2):726-729
This Letter describes the synthesis and evaluation of mGluR7 antagonists in the isoxazolopyridone series. In the course of modification in this class, novel solid support synthesis of the isoxazolopyridone scaffold was developed. Subsequent chemical modification led to the identification of several potent derivatives with improved physicochemical properties compared to a hit compound 1. Among these, 2 showed good oral bioavailability and brain penetrability, suggesting that 2 may be useful for in vivo study to elucidate the role of mGluR7. 相似文献