Abstract:
:We report analogues of N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Ilys-Pro-D-Ala- NH2, the parent antagonist (PA), which is a potent antagonist of LHRH. To simplify future radioactive labeling we prepared N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Arg-Pro-D-Ala-NH2 (4), [Arg8]PA, which had good activity in the antiovulatory assay (AOA). Other analogues were designed at first by substituting with Arg at positions 5, 6, 7, 9, and 10, and Trp or Leu at position 8. Subsequent analogues were prepared in attempts to improve the AOA of the initial ones. Substitutions with Arg9 or Arg10 led to analogues 1-3 with no AOA activity at 5 micrograms/rat. However, substitution with Arg7 gave 9, [Arg7,Leu8]PA, with significant activity in the AOA at 5 micrograms/rat and borderline activity at 2.5 micrograms/rat, and substitution with Ilys7 gave 13, [Ilys7,Leu8]PA, with borderline activity at 2 micrograms/rat, both analogues showing much weaker activity than PA in the histamine release assay (HRA) and therefore being potentially safer. Substitutions with D-Arg6 or Arg5 led to analogues with either good AO activity at 5 micrograms/rat (analogue 7) or with borderline activity at 5 micrograms/rat (analogue 8), although both were more potent than 6 in the HRA. Combinations of Ilys or Arg at positions 7 and 8 led to 10 and 11, both of which were tested at 2 micrograms/rat and found to have either good AO activity (analogue 10) or borderline activity (analogue 11) but unsuitably potent in HR. Substitutions using Ilys7 and neutral amino acids at position 8 led to 14-17 which were inactive in the AOA. Of great significance is the substitution with Arg7 yielding analogue 9, which was much safer in the HRA than analogue 4, [Arg8]PA. Analogues 9 and 13, featuring substitutions with the Arg7-Leu8 or Ilys7-Leu8 sequences were even safer than PA or 6 in the HRA. Analogue 12, [D-Trp3,Tyr5,D-Arg6,Arg7,Leu8]PA, featuring the Arg7-Leu8 sequence, had much lower potency in the HRA than [D-Trp3,Tyr5,D-Arg6,Leu7,Arg8]PA, which has the normal Leu7-Arg8 sequence. Ilys7 together with neutral amino acids at position 8 led to analogues 14-17 which were also very weak (safer) in the HRA, with the smaller amino acids Ala8 and Abu8 being the weakest of all analogues prepared.(ABSTRACT TRUNCATED AT 400 WORDS)
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Flouret G,Mahan K,Majewski Tdoi
10.1021/jm00082a004keywords:
subject
Has Abstractpub_date
1992-02-21 00:00:00pages
636-40issue
4eissn
0022-2623issn
1520-4804journal_volume
35pub_type
杂志文章abstract::Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00038a020
更新日期:1994-06-10 00:00:00
abstract::Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway of tryptophan metabolism, which is involved in immunity, neuronal function, and aging. Its implication in pathologies such as cancer and neurodegenerative diseases has stimulated the development of IDO1 inhibitors. However,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00942
更新日期:2019-10-10 00:00:00
abstract::Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01183
更新日期:2016-12-22 00:00:00
abstract::Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the centr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800321h
更新日期:2008-09-11 00:00:00
abstract::Two compounds, analogues of cephalexin with 2- and 4-pyridone groups at C-3, were prepared. Biological evaluation found the compounds to exhibit activity against Gram-positive and Gram-negative organisms in vitro and in vivo. The compounds were only active in vivo on subcutaneous administration. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00197a026
更新日期:1979-11-01 00:00:00
abstract::A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970547x
更新日期:1998-05-07 00:00:00
abstract::The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human DEDDh exonucleases can serve as antiviral drug targets due to their critical roles in virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00794
更新日期:2016-09-08 00:00:00
abstract::Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200409s
更新日期:2011-06-23 00:00:00
abstract::In a search for structurally new alpha(1)-adrenoreceptor (alpha(1)-AR) antagonists, prazosin (1)-related compounds 2-11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030952q
更新日期:2003-11-06 00:00:00
abstract::The synthesis and bioactivity of the retinoid X receptor (RXR) antagonist 4-[(3'-n-butyl-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'-naphthalenyl)(cyclopropylidene)methyl]benzoic acid and several heteroatom-substituted analogues are described. Ligand design was based on the scaffold of the 3'-methyl RXR-selectiv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030651g
更新日期:2004-08-26 00:00:00
abstract::We report twelve analogues of [Pmp1,D-Trp2,Arg8]oxytocin, ANTAG (Pmp = beta, beta-pentamethylene-beta-mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as measured in a uterotonic assay. Nine of the following analogues were designed by replacement of ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00111a025
更新日期:1991-07-01 00:00:00
abstract::In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0603623
更新日期:2006-11-02 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::The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0302039
更新日期:2003-12-18 00:00:00
abstract::A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 AR, which had bee...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701159t
更新日期:2008-03-27 00:00:00
abstract::The endocannabinoid hydrolyzing enzyme FAAH uses a nonclassical catalytic triad (namely, Ser-Ser-Lys instead of Ser-Asp-His) to cleave its endogenous substrates. Because inhibiting FAAH has a clear therapeutic potential, we previously developed β-lactam-type inhibitors of hFAAH. Here, we report the synthesis of five n...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200723m
更新日期:2011-10-13 00:00:00
abstract::Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501345y
更新日期:2015-01-22 00:00:00
abstract::The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the pare...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00170a008
更新日期:1990-08-01 00:00:00
abstract::Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701478a
更新日期:2008-06-26 00:00:00
abstract::Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00159
更新日期:2015-06-11 00:00:00
abstract::We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050907d
更新日期:2006-04-20 00:00:00
abstract::Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazol...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300573d
更新日期:2012-11-26 00:00:00
abstract::A series of conformationally locked N-glycosides having a cis-1,2-fused pyranose-1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhy...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm3006178
更新日期:2012-08-09 00:00:00
abstract::A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives, substituted at the 7-position with functionalized side chains, was synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) as well as ADP- and collagen-induced platelet aggregation, in vitro. Structural modificati...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00092a019
更新日期:1992-07-10 00:00:00
abstract::1-(Tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU), which is named Ftorafur or FT-207 and is used clinically as an antitumor agent, was conveniently synthesized by condensation of the trimethylsilyl derivative of 5-fluorouracil with 2-acetoxytetrahydrofuran using NaI as a catalyst. This optically inactive Thf-FU was res...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00222a011
更新日期:1977-12-01 00:00:00
abstract::The accessible surface, described by Lee and Richards (the L&R surface: J. Mol. Biol. 1971, 55, 379), has remarkably useful properties for displaying ligand-protein interactions. The surface is placed one van der Waals radius plus one probe radius away from the protein atoms. The ligands are displayed in skeletal form...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00088a002
更新日期:1992-05-15 00:00:00
abstract::Hydrogen sulfide (H2S) is now recognized as a physiologically important gasotransmitter. Compounds which release H2S slowly are sought after for their potential in therapy. Herein the synthesis of a series of phosphordithioates based on 1 (GYY4137) are described. Their H2S release profiles are characterized using 2,6-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00848
更新日期:2015-08-27 00:00:00
abstract::Regioselective syntheses of substituted 2-chloroquinoxalines and derived 2-(1-piperazinyl)quinoxalines are described. Selectivity in regards to serotonin reuptake blocking and serotoninmimetic activities of the piperazinylquinoxalines is reported. In general, introduction of a 6-substituent into the piperazinylquinoxa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00133a019
更新日期:1981-01-01 00:00:00
abstract::A series of eight C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (+-)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaborati...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00165a029
更新日期:1990-03-01 00:00:00
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 st...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00172a005
更新日期:1990-10-01 00:00:00