Biochemical mechanisms of drug action: what does it take for success?

@article{Swinney2004BiochemicalMO,
  title={Biochemical mechanisms of drug action: what does it take for success?},
  author={David C. Swinney},
  journal={Nature Reviews Drug Discovery},
  year={2004},
  volume={3},
  pages={801-808}
}
  • D. Swinney
  • Published 1 September 2004
  • Biology, Medicine
  • Nature Reviews Drug Discovery
Drug discovery is extremely difficult. There are many unanticipated scientific, medical and business challenges to every drug discovery programme. It is important to increase our understanding of the fundamental properties of effective drugs so that we can anticipate potential problems in developing new agents. This article addresses potential drug discovery and development risks associated with the biochemical mechanism of drug action, and proposes simple rules to minimize these risks. 
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References

SHOWING 1-10 OF 69 REFERENCES
The druggable genome
An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical…
Granisetron: relating pharmacology to clinical efficacy
  • P. Blower
  • Medicine
    Supportive Care in Cancer
  • 2002
TLDR
The pharmacology of granisetron suggests that it may have an improved side-effect and tolerability profile, a lower risk of drug interactions and a longer duration of action than other 5-HT3-receptor antagonists.
Enzyme Inhibition in Open Systems
TLDR
Investigations of the open system behavior of reversible dead-end inhibitors indicated that substrate-competitive inhibition may often be an inappropriate basis for design of potential therapeutic agents, and chemical analogs of pathogen-specific enzymic reaction products rather than analogS of substrates provide a promising basis for the systematic design of such uncompetitive inhibitors.
The Molecular Pharmacology of SERMs
  • D. McDonnell
  • Medicine, Biology
    Trends in Endocrinology & Metabolism
  • 1999
TLDR
Compounds of this class, which function as estrogens in the skeletal system but oppose estrogen action in the breast, are the first step in developing the perfect hormone replacement therapy.
A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors.
TLDR
A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme.
A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists.
TLDR
A new series of potent antagonists was designed, designed from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), and the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure, which was recently shown to also be active in cynomolgus monkeys both intravenously and orally.
Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays.
TLDR
The microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COx-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.
Progesterone receptor and the mechanism of action of progesterone antagonists
TLDR
Both published and unpublished data supporting the concept of two types of progesterone antagonists are discussed, suggesting that in addition to behaving by classical competitive mechanisms these compounds (in particular Type II) may exhibit additional activity as transrepressors of PR in the same cell bound to hormone agonist.
Evaluation of inhibition of the carbenicillin‐hydrolyzing β‐lactamase PSE‐4 by the clinically used mechanism‐based inhibitors
Characterization of the biochemical steps in the inactivation chemistry of clavulanic acid, sulbactam and tazobactam with the carbenicillin‐hydrolyzing β‐lactamase PSE‐4 from Pseudomonas aeruginosa…
Novel Mechanisms of Action of Three Antiepileptic Drugs, Vigabatrin, Tiagabine, and Topiramate
TLDR
Three currently available drugs are of special interest because they have novel mechanisms of action and are especially effective for partial onset seizures, and Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA.
...
1
2
3
4
5
...