Abstract:
:Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Murugesan N,Gu Z,Stein PD,Bisaha S,Spergel S,Girotra R,Lee VG,Lloyd J,Misra RN,Schmidt J,Mathur A,Stratton L,Kelly YF,Bird E,Waldron T,Liu EC,Zhang R,Lee H,Serafino R,Abboa-Offei B,Mathers P,Giancarli M,Seymoudoi
10.1021/jm970872ksubject
Has Abstract,Author List Incompletepub_date
1998-12-17 00:00:00pages
5198-218issue
26eissn
0022-2623issn
1520-4804pii
jm970872kjournal_volume
41pub_type
杂志文章abstract::The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows p...
journal_title:Journal of medicinal chemistry
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abstract::An approach to the development of new anticandidal drugs is described that employs peptides as carriers of toxic agents into cells. 5-Flurorcytosine (5-FC) was chosen as a toxic agent with which to prepare 5-FC-peptide conjugates as models to test the carrier proposal. Model compounds were synthesized and then tested ...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00195a019
更新日期:1979-09-01 00:00:00
abstract::Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzym...
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abstract::Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the se...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00099a004
更新日期:1992-10-16 00:00:00
abstract::In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the...
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abstract::A novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids was synthesized to investigate the influence of different hydrogen-bond donor and acceptor groups at this specific position on the affinity to the glycine site of the NMDA receptor. These novel 3-indolylmethyl derivatives with ring-open (amines, s...
journal_title:Journal of medicinal chemistry
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abstract::Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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abstract::A series of 3-hydroxy-substituted analogues (3-7) of the mu selective opioid antagonist cyprodime has been synthesized in order to evaluate the role of a hydroxy group at C-3 concerning mu opioid antagonist selectivity. Compounds 3-7 were tested in bioassays (electrical stimulated mouse vas deferens preparation and my...
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doi:10.1021/jm00016a010
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abstract::Bis (1-aziridinyl)(hexahydro-1H-azepin-1-yl)phosphine sulfide, an active anticancer agent with low hematopoietic toxicity in animals and man, was recommended several years ago for breast cancer adjuvant chemotherapy as an alternate drug to thiotepa. This hope had led to the syntheses of aziridinylallylaminophosphine o...
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pub_type: 杂志文章
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abstract::Opical antipodes of the axial phenyl analgetic, alpha-promedol hydrochloride (3), were prepared and the absolute stereochemistry wasd determined by relating one of the enantiomers to its gamme diastereomer having the 2S, 4S,5R configuration. The analegetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, whil...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00231a014
更新日期:1976-09-01 00:00:00
abstract::The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper,...
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00030a012
更新日期:1994-02-18 00:00:00
abstract::The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00377a021
更新日期:1984-11-01 00:00:00
abstract::Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot...
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abstract::cis-4-Hydroperoxycyclophosphamide (5) undergoes facile reaction with aqueous phosphate or Tris buffers at pH 7-8 and 30 degrees C. The kinetics of 5 are complex, and the trans-4-hydroperoxy isomer 6 is produced and subsequently disappears over the course of the reaction. Addition of hydrogen peroxide to the reaction m...
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pub_type: 杂志文章
doi:10.1021/jm00370a009
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abstract::A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules t...
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journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00177a024
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abstract::Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5...
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journal_title:Journal of medicinal chemistry
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