Fluorine in Medicinal Chemistry

Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D‐structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein–ligand interactions that involve fluorine.

[1]  H. Davis,et al.  In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. , 1997, The Journal of pharmacology and experimental therapeutics.

[2]  H. Koga,et al.  Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids. , 1980, Journal of medicinal chemistry.

[3]  P. Wolschann,et al.  On the structure and torsional potential of trifluoromethoxybenzene: an ab initio and density functional study , 2003 .

[4]  J. Clader.  The discovery of ezetimibe: a view from outside the receptor. , 2004, Journal of medicinal chemistry.

[5]  Xinjian Yan,et al.  Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. , 1996, Biochemistry.

[6]  T. Maren,et al.  A new class of carbonic anhydrase inhibitor. , 1993, The Journal of biological chemistry.

[7]  H. Waterbeemd,et al.  Pharmacokinetics and Metabolism in Drug Design: Smith: Pharmacokinetics , 2001 .

[8]  W. E. Barnette.  The synthesis and biology of fluorinated prostacyclins. , 1984, CRC critical reviews in biochemistry.

[9]  R. Kurumbail,et al.  Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. , 2003, Bioorganic & medicinal chemistry letters.

[10]  C. C. Kotoris,et al.  Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. , 1998, Bioorganic & medicinal chemistry letters.

[11]  Ericka Stricklin-Parker,et al.  Ann , 2005 .

[12]  Gordon M. Crippen,et al.  Prediction of Physicochemical Parameters by Atomic Contributions , 1999, J. Chem. Inf. Comput. Sci..

[13]  R. Kurumbail,et al.  Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. , 2003, Journal of medicinal chemistry.

[14]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[15]  J. Snyder,et al.  Protonated 3-fluoropiperidines: an unusual fluoro directing effect and a test for quantitative theories of solvation , 1993 .

[16]  B. Smart.  Fluorine substituent effects (on bioactivity) , 2001 .

[17]  R. S. Rogers,et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). , 1997, Journal of medicinal chemistry.

[18]  D. Davey,et al.  Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[19]  A. Bondi.  van der Waals Volumes and Radii , 1964 .

[20]  A. Pike,et al.  Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles. , 1999, Journal of medicinal chemistry.

[21]  Paul Seiler,et al.  A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F...C=O interactions. , 2003, Angewandte Chemie.

[22]  B. Sweatman,et al.  Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in rabbit, mouse and human: identification of fluorine NIH shift metabolites using NMR and tandem MS , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[23]  D. Christianson,et al.  Fluoroaromatic-fluoroaromatic interactions between inhibitors bound in the crystal lattice of human carbonic anhydrase II. , 2001, Journal of the American Chemical Society.

[24]  A. Beatty,et al.  Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors. , 1999, Journal of medicinal chemistry.

[25]  N. Kitteringham,et al.  Metabolism of fluorine-containing drugs. , 2001, Annual review of pharmacology and toxicology.

[26]  J. Domagala,et al.  New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay. , 1986, Journal of medicinal chemistry.

[27]  Chu-Young Kim,et al.  Contribution of Fluorine to Protein−Ligand Affinity in the Binding of Fluoroaromatic Inhibitors to Carbonic Anhydrase II , 2000 .

[28]  S. Chakravarty.  Chapter 18. Inhibitors of p38α MAP kinase , 2002 .

[29]  R. Kurumbail,et al.  Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. , 2003, Journal of medicinal chemistry.

[30]  C. Swain,et al.  Chapter 6. Progress in the Development of Neurokinin Antagonists , 1999 .

[31]  C. Supuran,et al.  Carbonic Anhydrase Inhibitors: X-ray Crystallographic Structure of the Adduct of Human Isozyme II with the Perfluorobenzoyl Analogue of Methazolamide. Implications for the Drug Design of Fluorinated Inhibitors , 2003, Journal of enzyme inhibition and medicinal chemistry.

[32]  J. Vervoort,et al.  Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. , 1998, Chemical research in toxicology.

[33]  J. Boehm,et al.  1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. , 1996, Journal of medicinal chemistry.

[34]  M. Bols,et al.  Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines. , 2002, Chemistry.

[35]  J. Doyon,et al.  The pattern of fluorine substitution affects binding affinity in a small library of fluoroaromatic inhibitors for carbonic anhydrase. , 1999, Organic letters.

[36]  H. Rzepa,et al.  Some influences of fluorine in bioorganic chemistry , 1997 .

[37]  Robin Taylor,et al.  Organic Fluorine Hardly Ever Accepts Hydrogen Bonds , 1997 .

[38]  B. Witherbee,et al.  Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaryamino)-2-propanols as potent inhibitors of cholesteryl ester transfer protein. , 2001, Bioorganic & medicinal chemistry letters.