共查询到20条相似文献,搜索用时 0 毫秒
1.
Colin M. Tice Zhenrong Xu Jing Yuan Robert D. Simpson Salvacion T. Cacatian Patrick T. Flaherty Wei Zhao Joan Guo Alexey Ishchenko Suresh B. Singh Zhongren Wu Boyd B. Scott Yuri Bukhtiyarov Jennifer Berbaum Jennifer Mason Reshma Panemangalore Maria Grazia Cappiello Dominik Müller Richard K. Harrison Gerard M. McGeehan David A. Claremon 《Bioorganic & medicinal chemistry letters》2009,19(13):3541-3545
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(4):1026-1030
Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring. DMPK study of one of the active compounds has shown a moderate oral PK and reasonable bioavailability. 相似文献
3.
Pissarnitski DA Asberom T Bara TA Buevich AV Clader JW Greenlee WJ Guzik HS Josien HB Li W McEwan M McKittrick BA Nechuta TL Parker EM Sinning L Smith EM Song L Vaccaro HA Voigt JH Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(1):57-62
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned. 相似文献
4.
Tite T Lallemand MC Poupon E Kunesch N Tillequin F Gravier-Pelletier C Le Merrer Y Husson HP 《Bioorganic & medicinal chemistry》2004,12(19):5091-5097
A series of 16 new chiral nonracemic polyhydroxylated piperidines was synthesized utilizing several chiral beta-amino-alcohols. They act as a nitrogen source, chirality inducer and iminium stabilizer, in the desymmetrization of meso-trihydroxylated glutaraldehyde. The biological activity of these compounds towards several glycosidases (alpha-D-glucosidase, alpha-D-mannosidase, alpha-L-fucosidase) has been evaluated. 相似文献
5.
Olivier Corminboeuf Olivier Bezençon Ľuboš Remeň Corinna Grisostomi Sylvia Richard-Bildstein Daniel Bur Lars Prade Panja Strickner Patrick Hess Walter Fischli Beat Steiner Alexander Treiber 《Bioorganic & medicinal chemistry letters》2010,20(21):6291-6296
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described. 相似文献
6.
Li H Asberom T Bara TA Clader JW Greenlee WJ Josien HB McBriar MD Nomeir A Pissarnitski DA Rajagopalan M Xu R Zhao Z Song L Zhang L 《Bioorganic & medicinal chemistry letters》2007,17(22):6290-6294
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. 相似文献
7.
Scheiper B Matter H Steinhagen H Böcskei Z Fleury V McCort G 《Bioorganic & medicinal chemistry letters》2011,21(18):5480-5486
The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3 nM. 相似文献
8.
Bodo Scheiper Hans Matter Henning Steinhagen Ulrich Stilz Zsolt Böcskei Valérie Fleury Gary McCort 《Bioorganic & medicinal chemistry letters》2010,20(21):6268-6272
Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin–angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC50 value of 2 nM. 相似文献
9.
Lacombe P Arbour M Aspiotis R Cauchon E Chen A Dubé D Falgueyret JP Fournier PA Gallant M Grimm E Han Y Juteau H Liu S Mellon C Ramtohul Y Simard D St-Jacques R Tsui GC 《Bioorganic & medicinal chemistry letters》2012,22(5):1953-1957
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species. 相似文献
10.
Sund C Belda O Wiktelius D Sahlberg C Vrang L Sedig S Hamelink E Henderson I Agback T Jansson K Borkakoti N Derbyshire D Eneroth A Samuelsson B 《Bioorganic & medicinal chemistry letters》2011,21(1):358-362
Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the Ki and the human plasma renin activity (HPRA)IC50 was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (Ki = 3.3 nM and HPRA IC50 = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (Ki = 34 nM and HPRA IC50 = 56 nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin. 相似文献
11.
Austin Chen Christopher Bayly Olivier Bezençon Sylvia Richard-Bildstein Daniel Dubé Laurence Dubé Sébastien Gagné Michel Gallant Mireille Gaudreault Erich Grimm Robert Houle Patrick Lacombe Sébastien Laliberté Jean-François Lévesque Suzanna Liu Dwight MacDonald Bruce Mackay David Martin Dan McKay David Powell Sylvie Toulmond 《Bioorganic & medicinal chemistry letters》2010,20(7):2204-2209
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model. 相似文献
12.
Amos B. Smith Ryouichi Akaishi David R. Jones Terence P. Keenam Mark C. Guzman Ryan C. Holcomb Paul A. Sprengeler John L. Wood Ralph Hirschmann M. Katharine Holloway 《Biopolymers》1995,37(1):29-53
The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous amide scaffold which incorportated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC50s in the 0.6 to 18 μM range. These compounds did not inhibit HIV-1 protease. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin. © 1994 John Wiley & Sons, Inc. 相似文献
13.
Fournier PA Arbour M Cauchon E Chen A Chefson A Ducharme Y Falgueyret JP Gagné S Grimm E Han Y Houle R Lacombe P Lévesque JF MacDonald D Mackay B McKay D Percival MD Ramtohul Y St-Jacques R Toulmond S 《Bioorganic & medicinal chemistry letters》2012,22(8):2670-2674
The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential. 相似文献
14.
G J Hanson J S Baran T Lindberg G M Walsh S E Papaioannou M Babler S E Bittner P C Yang M Dal Corobbo 《Biochemical and biophysical research communications》1985,132(1):155-161
The discovery of a new class of novel renin inhibitors consisting of protected dipeptide amides derived from aminoglycols (Formula I) prompted a study of structure-activity in vitro and efficacy in vivo. Thus, Boc-L-Phe-N-[(1S,2R)-1-benzyl-(2,3-dihydroxy)propyl]-L-leucinamide (1) and the corresponding histidinamide (2) inhibit human renin in vitro (IC50: 8.7 X 10-6 M and 2.6 X 10-6 M, respectively). Compound 1 has a slight inhibitory effect on pepsin and compound 2 does not inhibit pepsin at all (at 10-4M); these compounds are inactive against rat renin. Compound 1 is efficacious in lowering plasma renin activity in the Rhesus monkey (i.v.). Results indicate that this new class of low molecular weight inhibitors is specific for human renin and thus constitutes a new source of drug candidates. 相似文献
15.
Holsworth DD Cai C Cheng XM Cody WL Downing DM Erasga N Lee C Powell NA Edmunds JJ Stier M Jalaie M Zhang E McConnell P Ryan MJ Bryant J Li T Kasani A Hall E Subedi R Rahim M Maiti S 《Bioorganic & medicinal chemistry letters》2006,16(9):2500-2504
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity. 相似文献
16.
17.
Escribano A Mateo AI Martin de la Nava EM Mayhugh DR Cockerham SL Beyer TP Schmidt RJ Cao G Zhang Y Jones TM Borel AG Sweetana SA Cannady EA Mantlo NB 《Bioorganic & medicinal chemistry letters》2012,22(11):3671-3675
This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties. 相似文献
18.
K Y Hui H M Siragy E Haber 《International journal of peptide and protein research》1992,40(2):152-160
Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect. 相似文献
19.
Gundersen E Fan K Haas K Huryn D Steven Jacobsen J Kreft A Martone R Mayer S Sonnenberg-Reines J Sun SC Zhou H 《Bioorganic & medicinal chemistry letters》2005,15(7):1891-1894
Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database. 相似文献
20.
Human renin inhibitors 总被引:1,自引:0,他引:1
B J Leckie M Szelke B Atrash S R Beattie A Hallett D M Jones G D McIntyre J Suerias D J Webb 《Biochemical Society transactions》1985,13(6):1029-1032