Abstract:
:Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration of drugs, equations have been derived from a combination of mass law, equilibrium, and extrathermodynamic assumptions. In general form the equations which relate potency to partition coefficient (P) and degree of ionization (alpha) are the following. If the neutral form reacts with the receptor, log (1/C) =-log [1 + SIGMAM(DIPci) + sigman[aj/Pb(1-alpha4y]] + X. If the ionic form reacts with the receptor, log (1/C) =-log [1 + (1 - Alphan)/(alphan)[sigmam(diPci) + sigman[aj/Pb(1-alphaj)]]] + X. In this generalized model there are m nonaqueous compartments and n aqueous compartments of different pH. The parameters a, b, c, and d can be interpreted in terms of the model. The shape of the log (1/C) vs. log P curve may be asymptotic, linear, or composed of two portions of unequal slope which meet at an optimum or a bend. With the use of these equations it is possible to examine whether the ion or the neutral form is the active species and whether there is hydrophobic bonding to the receptor and/or an inert compartment. The models may be further extended to include terms other than log P and alpha.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Martin YC,Hackbarth JJdoi
10.1021/jm00230a012subject
Has Abstractpub_date
1976-08-01 00:00:00pages
1033-9issue
8eissn
0022-2623issn
1520-4804journal_volume
19pub_type
杂志文章abstract::Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease se...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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journal_title:Journal of medicinal chemistry
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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...
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journal_title:Journal of medicinal chemistry
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更新日期:1993-10-29 00:00:00
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journal_title:Journal of medicinal chemistry
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journal_title:Journal of medicinal chemistry
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更新日期:1984-07-01 00:00:00
abstract::Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood--brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl es...
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abstract::Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and...
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:1995-06-09 00:00:00
abstract::A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00211a004
更新日期:1977-01-01 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
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更新日期:2016-03-24 00:00:00
abstract::Selective inhibitors of protein tyrosine phosphatases (PTPs) and dual-specificity phosphatases (DSPs) are expected to be useful tools for clarifying the biological functions of the PTPs themselves and also to be candidates for novel therapeutics. We planned a library approach for the identification of PTP/DSP inhibito...
journal_title:Journal of medicinal chemistry
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journal_title:Journal of medicinal chemistry
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更新日期:1996-05-24 00:00:00
abstract::We recently discovered the isoform selective RAR beta 2 ligand 4'-octyl-4-biphenylcarboxylic acid (3, AC-55649). Although 3 is highly potent at RAR beta 2 and displays excellent selectivity, solubility issues make it unsuitable for drug development. Herein we describe the exploration of the SAR in a biphenyl and a phe...
journal_title:Journal of medicinal chemistry
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更新日期:2009-03-26 00:00:00
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更新日期:2000-11-16 00:00:00
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journal_title:Journal of medicinal chemistry
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abstract::Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title:Journal of medicinal chemistry
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更新日期:2020-09-24 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2018-02-22 00:00:00
abstract::2-Alkylchromen-4-one 6-O-sulfamates, a new class of potent steroid sulfatase (STS) inhibitors, were evaluated for their estrogenic potential. Structure-activity relationships for estrogenic activity were identified; however, no correlation with STS inhibition was found. Estrogenicity is favored by bulky side chains an...
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pub_type: 杂志文章
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更新日期:2003-11-06 00:00:00
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更新日期:2005-01-13 00:00:00