Abstract：
:The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Yamada K,Levell J,Yoon T,Kohls D,Yowe D,Rigel DF,Imase H,Yuan J,Yasoshima K,DiPetrillo K,Monovich L,Xu L,Zhu M,Kato M,Jain M,Idamakanti N,Taslimi P,Kawanami T,Argikar UA,Kunjathoor V,Xie X,Yagi YI,Iwaki Y,Rodoi
10.1021/acs.jmedchem.7b00708subject
Has Abstractpub_date
2017-08-24 00:00:00pages
7099-7107issue
16eissn
0022-2623issn
1520-4804journal_volume
60pub_type
杂志文章abstract：:Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00034a016
更新日期：1994-04-15 00:00:00
abstract：:We studied the structure-activity relationships of a series of 2'-fluoro-2',3'-unsaturated D-nucleosides against HIV-1 in human peripheral blood mononuclear (PBM) cells. The target compounds 10-21 and 28-33 were prepared by N-glycosylation of the acetate 4, which was readily prepared from 2,3-O-isopropylidene-D-glycer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010418n
更新日期：2002-03-14 00:00:00
abstract：:Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400349k
更新日期：2013-05-23 00:00:00
abstract：:A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00051a005
更新日期：1994-12-09 00:00:00
abstract：:A series of 3-methyl-3-(m-hydroxyphenyl)piperidines with N-substituent variations have been synthesized and resolved, and an X-ray crystal structure of one analogue was determined. The compounds have been characterized, pharmacologically, by detailed opiate receptor binding studies and determination of in vivo analges...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00154a018
更新日期：1986-04-01 00:00:00
abstract：:A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01446
更新日期：2019-12-26 00:00:00
abstract：:The superior activity of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (MeCCNU) against advanced murine Lewis lung carcinoma in comparisons with the cis form and other nitrosoureas prompted the synthesis of a number of MeCCNU analogues, including several cis-trans pairs. The methyl group was replaced b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00212a019
更新日期：1977-02-01 00:00:00
abstract：:Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a n...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01607
更新日期：2018-02-22 00:00:00
abstract：:A series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines were synthesized and tested for their ability to inhibit the binding of [3H]diazepam to rat brain receptors in vitro. Compounds bearing a phenyl, 4-methoxyphenyl, or methyl group at position 3 and a dialkylamino group at position 6 showed the highest affinit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00147a034
更新日期：1985-09-01 00:00:00
abstract：:At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm5006463
更新日期：2014-10-09 00:00:00
abstract：:Substrate-selective inhibition or modulation of the activity of γ-secretase, which is responsible for the generation of amyloid-β peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical β-peptide foldamers are potent and specific inhibitors of γ-secretas...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301306c
更新日期：2013-02-28 00:00:00
abstract：:We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0499559
更新日期：2004-05-20 00:00:00
abstract：:The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and incurable neurodegenerative disorders primarily afflicting the pediatric population. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.5b01020
更新日期：2016-05-26 00:00:00
abstract：:In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic sta...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00245
更新日期：2016-07-28 00:00:00
abstract：:A variety of 2,3-disubstituted 5,7-dimethyl-1,8-naphthyridines was synthesized and tested in saline-loaded rats for their diuretic properties. The 2-amino-3-carbomethoxy and four 2-amino-3-N-alkylcarbamoyl compounds exhibited significant activity as measured by volume output; however, they were generally less potent t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00216a021
更新日期：1977-06-01 00:00:00
abstract：:Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01395
更新日期：2017-11-09 00:00:00
abstract：:We report the results of a three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore modeling investigation of the interaction of the enzyme 3-phosphoglycerate kinase (PGK) with aryl and alkyl bisphosphonates. For the human enzyme, the IC50 values are predicted within a factor of 2 ove...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0604833
更新日期：2006-11-16 00:00:00
abstract：:Intrigued by the role of protein acetylation in hepatitis C virus (HCV) replication, we tested known histone deacetylase (HDAC) inhibitors and a focused library of structurally simple hydroxamic acids for inhibition of a HCV subgenomic replicon. While known HDAC inhibitors with varied inhibitory profiles proved to be ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501330g
更新日期：2015-01-22 00:00:00
abstract：:Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030091l
更新日期：2003-06-19 00:00:00
abstract：:Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resista...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00640
更新日期：2016-09-08 00:00:00
abstract：:Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0509997
更新日期：2006-02-09 00:00:00
abstract：:9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300642a
更新日期：2013-03-14 00:00:00
abstract：:Thrombin is a serine protease responsible for blood coagulation. Since thrombin inhibitors appear to be effective in the treatment and prevention of thrombotic and embolic disorders, considerable attention has been focused on the structure and interactions of this enzyme. In this work, to evaluate the relative free en...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020123p
更新日期：2002-11-07 00:00:00
abstract：:Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070383c
更新日期：2007-07-12 00:00:00
abstract：:Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) canc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5019115
更新日期：2015-03-12 00:00:00
abstract：:The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0004998
更新日期：2001-05-10 00:00:00
abstract：:A computational methodology is introduced to systematically organize compound analogue series according to substitution sites and identify combinations of sites that determine structure-activity relationships (SARs) and make large contributions to SAR discontinuity. These sites are prime targets for further chemical m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900107b
更新日期：2009-05-28 00:00:00
abstract：:Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0301787
更新日期：2003-10-23 00:00:00
abstract：:A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were prepared as potential peroxide antimalarial agents. In both series of cyclic peroxides, the steric and electronic effects of the substituents attached to the peroxide ring exert a remarkable influence on the antimalarial activity. For some cycli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990014j
更新日期：1999-07-15 00:00:00
abstract：:A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-pi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000305o
更新日期：2000-11-16 00:00:00
