Abstract:
:A three-dimensional structure of the complex of human renin and the scissile site P4 Pro to P1' Val of angiotensinogen was deduced in order to design potent human renin inhibitors rationally. On the basis of this structure, an orally potent human renin inhibitor (1a) was designed from the angiotensinogen transition state and synthesized. The inhibitor 1a contains a (2R)-3-(morpholinocarbonyl)-2-(1-naphthylmethyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and a novel amino acid, (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid, named cyclohexylnorstatine (2a). The optically pure cyclohexylnorstatine was efficiently prepared from Boc-L-cyclohexylalaninol (3), and the stereochemistry of 1a was established by X-ray crystal analysis. The analyses of interaction between 1a and human renin using modeling techniques indicated that (1) the cyclohexyl group of P1 and the naphthyl group of P3 were accommodated in large hydrophobic subsites S1 and S3, respectively; (2) the imidazole of P2 His was hydrogen bonded to the side chain OH of Ser-233 to contribute to the selectivity of renin inhibition; (3) cyclohexylnorstatine isopropyl ester residue was accommodated in S1-S1'. The importance of the stereochemistry in the potent and specific inhibitor was clearly shown. Oral administration to monkeys of this inhibitor resulted in a drop of 10-20 mmHg in mean blood pressure and a reduction of plasma renin activity for a 5-h period.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Iizuka K,Kamijo T,Harada H,Akahane K,Kubota T,Umeyama H,Ishida T,Kiso Ydoi
10.1021/jm00172a005subject
Has Abstractpub_date
1990-10-01 00:00:00pages
2707-14issue
10eissn
0022-2623issn
1520-4804journal_volume
33pub_type
杂志文章abstract::Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. C...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970275y
更新日期:1997-10-24 00:00:00
abstract::Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were us...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050441z
更新日期:2005-08-25 00:00:00
abstract::The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neur...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00609
更新日期:2016-07-14 00:00:00
abstract::By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0103099
更新日期:2002-01-03 00:00:00
abstract::The effects of 3-position substitution of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on 5-HT 2A receptor affinity were determined and compared to a parallel series of DOB-like 1-(2,5-dimethoxyphenyl)-2-aminopropanes substituted at the 4-position. The results were interpreted within the context of 5-HT 2A receptor mod...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800771x
更新日期:2008-11-13 00:00:00
abstract::A set of 2,4-diamino-5-(3-X-phenyl)-s-triazines was used to inhibit the growth of tumor cells (L5178 leukemia) in culture. The molar concentration (C) of triazine causing 50% reduction in the rate of cell growth was used to develop a quantitative structure-activity relationship: log 1/C = 1.32 pi - 1.70 log (beta.10 p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00344a012
更新日期:1982-02-01 00:00:00
abstract::From the results of our previous physicochemical studies of polyamine-nucleic acid interactions, we concluded that polyamine analogues in cisoidal conformation are capable of wrapping around the major groove of the double helix, of displacing natural polyamines from their nucleic acid binding sites, and of inhibiting ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000310s
更新日期:2001-02-01 00:00:00
abstract::The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as w...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200464w
更新日期:2011-07-14 00:00:00
abstract::Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00260
更新日期:2019-07-25 00:00:00
abstract::A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liqui...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm991056a
更新日期:2000-03-23 00:00:00
abstract::The first example of vinca derivatives 16-18 able to modulate P-glycoprotein (Pgp) efflux activity is reported. They were elaborated in two steps from vinorelbine 3 (VLN) by a modification of the velbenamine moiety. These compounds were able to decrease efficiently Pgp mediated influx and efflux of rhodamine-123 (Rho)...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00525
更新日期:2016-12-08 00:00:00
abstract::We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200536d
更新日期:2011-08-25 00:00:00
abstract::Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049035q
更新日期:2005-04-07 00:00:00
abstract::A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structur...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00130a022
更新日期:1989-10-01 00:00:00
abstract::Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01682
更新日期:2019-02-28 00:00:00
abstract::The synthesis of a new class of multisubstrate adduct inhibitors of polyamine biosynthesis has been investigated. The first target compound, designed to inhibit spermidine synthase, was obtained and proved to be a very potent inhibitor of that enzyme. Two synthetic routes to effect the coupling of the polyamine spermi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00014a023
更新日期:1995-07-07 00:00:00
abstract::Transient receptor potential canonical (TRPC) channels are highly homologous, nonselective cation channels that form many homo- and heterotetrameric channels. These channels are highly abundant in the brain and kidney and have been implicated in numerous diseases, such as depression, addiction, and chronic kidney dise...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b01954
更新日期:2019-09-12 00:00:00
abstract::The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm3012239
更新日期:2012-11-26 00:00:00
abstract::Random screening of compounds in an ETA receptor binding assay led to the discovery of a class of benzenesulfonamide ligands. Optimization led to the development of 5-amino-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamides which were functional antagonists. Structural features which were important to activity in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00008a013
更新日期:1995-04-14 00:00:00
abstract::Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b00370
更新日期:2018-09-27 00:00:00
abstract::A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00164a021
更新日期:1990-02-01 00:00:00
abstract::Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitor...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00791
更新日期:2018-09-13 00:00:00
abstract::The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for certain neurological diseases. In particular, the DAT is depleted in Parkinson's disease, and the extent of depletion correlates with the loss of dopamine. Herein we describe the design, synthesis, and biological evaluat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960868t
更新日期:1997-06-06 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::In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm4001242
更新日期:2013-07-11 00:00:00
abstract::Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00275
更新日期:2017-12-28 00:00:00
abstract::The potent inhibitory activity of novel 2-benzyltetralone and 2-benzylidenetetralone derivatives vs liver microsomal retinoic acid metabolizing enzymes and a MCF-7 CYP26A1 cell assay is described. In the liver microsomal assay, the 2-biphenylmethyl-6-hydroxytetralone derivatives 16a and 16b were found to be potent inh...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0501681
更新日期:2005-11-17 00:00:00
abstract::New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangos...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01348
更新日期:2017-12-28 00:00:00
abstract::RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200161c
更新日期:2011-07-14 00:00:00
abstract::A library of approximately 2000 small molecules biased toward inhibition of histone deacetylases was assayed for antimalarial activity in a high-throughput P. falciparum viability assay. Active compounds were cross-analyzed for induction of histone hyperacetylation in a human myeloma cell line to identify HDAC inhibit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801654y
更新日期:2009-04-23 00:00:00