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, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3-or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Fries DF,Portoghese PSdoi
10.1021/jm00231a014subject
Has Abstractpub_date
1976-09-01 00:00:00pages
1155-8issue
9eissn
0022-2623issn
1520-4804journal_volume
19pub_type
杂志文章abstract：:The principle of bioisosterism-similarly shaped molecules are more likely to share biological properties than are other molecules-has long helped to guide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990159q
更新日期：1999-09-23 00:00:00
abstract：:Several imidazolylphenyl sulfamate and (imidazolylphenoxy)alkyl sulfamate derivatives were synthesized and evaluated as topically active carbonic anhydrase inhibitors. Water solubility, pKa, carbonic anhydrase inhibition, and partition coefficient for the compounds were measured. Sulfamic acid 2-[4-(1H-imidazol-1-yl)p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00104a003
更新日期：1992-12-25 00:00:00
abstract：:The synthesis of hybrid "cationic metalloporphyrin-intercalator" molecules is reported. These molecules are based on 9-methoxyellipticine as intercalator and tris-(4-N-methylpyridiniumyl)metalloporphyrins having a 4-aminophenyl or a 4-hydroxyphenyl group for the attachment of the linker. The effect of the length of li...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00107a005
更新日期：1991-03-01 00:00:00
abstract：:Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthra...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0497040
更新日期：2004-11-18 00:00:00
abstract：:Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of rever...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030373l
更新日期：2004-01-29 00:00:00
abstract：:A series of cis- and trans-6,6a,7,8,9,10,10a,11-octahydro-11- oxodibenzo[b,e]thiepinacetic acids (6-9) and -oxepinacetic acids (10-13) were prepared and their antiinflammatory activity was examined in the rat carrageenan hind paw edema test. The antiinflammatory activity of these compounds depended on their stereochem...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a006
更新日期：1990-02-01 00:00:00
abstract：:The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most pote...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501792c
更新日期：2015-02-26 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：:A novel series of diaminoanthraquinones was discovered initially as protein kinase C inhibitors with IC50s in the 50-100 microM range. They exhibited potent tumor cell growth inhibitory activity in vitro without cross resistance to adriamycin. Further evaluation of two of the most active compounds NSC 639365 (3) and N...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00101a001
更新日期：1992-11-13 00:00:00
abstract：:To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been de...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020839k
更新日期：2002-09-12 00:00:00
abstract：:A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive bindin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049554t
更新日期：2004-11-04 00:00:00
abstract：:A practical combination of comparative modeling and NMR spectroscopy was used to generate a three-dimensional structure of the response regulator protein, Spo0F. The backbone structure obtained compares to the Spo0F Y13S mutant X-ray structure with an rmsd of 2.0 A. We provide results which suggest that structures obt...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970156i
更新日期：1997-10-10 00:00:00
abstract：:The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted toward the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regul...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b01346
更新日期：2018-01-25 00:00:00
abstract：:A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100884b
更新日期：2010-10-28 00:00:00
abstract：:Appropriately protected nucleoside 5'-O-(2-thio-1,3,2-dithiaphospholanes) react with inorganic pyrophosphate in the presence of a strong base catalyst (DBU) to give nucleoside 5'-O-(1,1-dithiotriphosphates) 1a-g. The latter compounds, including an AZT analogue, show modest antivirial activity against HIV-1 and HIV-2 r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00048a021
更新日期：1994-10-28 00:00:00
abstract：:Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX09...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01750
更新日期：2019-03-28 00:00:00
abstract：:The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-ac...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501400p
更新日期：2014-11-13 00:00:00
abstract：:Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their development. We have designed a new Ru(II) PDT candidate that efficiently enters cells by incorporation of the lipophilic ar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00451
更新日期：2015-06-11 00:00:00
abstract：:A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a020
更新日期：1985-02-01 00:00:00
abstract：:Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dop...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00169a016
更新日期：1990-07-01 00:00:00
abstract：:A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compoun...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01279
更新日期：2018-01-11 00:00:00
abstract：:In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901782m
更新日期：2010-04-22 00:00:00
abstract：:A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00046a006
更新日期：1994-09-30 00:00:00
abstract：:HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00994
更新日期：2016-12-22 00:00:00
abstract：:Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00343
更新日期：2017-06-22 00:00:00
abstract：:A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00084a014
更新日期：1992-03-20 00:00:00
abstract：:Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds cov...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901558p
更新日期：2010-03-11 00:00:00
abstract：:A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-positi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0611509
更新日期：2007-03-08 00:00:00
abstract：:Spatial correspondence between apomorphine, a prototype dopaminergic (DA) drug, and ergoline and some of its (partial) analogues were derived by matching their molecular electrostatic potential (MEP) patterns surrounding the aromatic moieties with respect to the coincident aliphatic N atoms. The MEP patterns were calc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00158a017
更新日期：1986-08-01 00:00:00
abstract：:A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) recep...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm001124p
更新日期：2001-06-07 00:00:00
