A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pKa and binding affinity and evidence for intermolecular C-F...CN interactions.

The H-atoms of the phenylamidinium needle of tricyclic thrombin inhibitors, which interacts with Asp189 at the bottom of the selectivity pocket S1 of the enzyme, were systematically exchanged with F-atoms in an attempt to improve the pharmacokinetic properties by lowering the pK(a) value. Both the pK(a) values and the inhibitory constants K(i) against thrombin and trypsin were decreased upon F-substitution. Interestingly, linear free energy relationships (LFERs) revealed that binding affinity against thrombin is much more affected by a decrease in pK(a) than the affinity against trypsin. Surprising effects of F-substitutions in the phenylamidinium needle on the pK(a) value of the tertiary amine centre in the tricyclic scaffold of the inhibitors were observed and subsequently rationalised by X-ray crystallographic analysis and ab initio calculations. Evidence for highly directional intermolecular C-F...CN interactions was obtained by analysis of small-molecule X-ray crystal structures and investigations in the Cambridge Structural Database (CSD).

[1]  D. Musil,et al.  Synthesis and SAR of thrombin inhibitors incorporating a novel 4-amino-morpholinone sscaffold: analysis of X-ray crystal structure of enzyme inhibitor complex. , 2003, Journal of medicinal chemistry.

[2]  S. Lancaster,et al.  Intra- and inter-molecular C-H...F-C and N-H...F-C hydrogen bonding in secondary amine adducts of B(C6F5)3: relevance to key interactions in alkene polymerisation catalysis. , 2003, Chemical communications.

[3]  C. Park,et al.  Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide. , 2003, Journal of medicinal chemistry.

[4]  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.

[5]  T. Schrader,et al.  Molecular recognition of amidines in water. , 2003, Organic letters.

[6]  F. Diederich,et al.  Interactions with aromatic rings in chemical and biological recognition. , 2003, Angewandte Chemie.

[7]  W. M. Sanders,et al.  Azaindoles: moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[8]  W. Marshall,et al.  Is fluoride bonded to two Pd acceptors still basic? Three CH2Cl2 molecules encapsulating a Pd2(mu-F)2 square and new implications for catalysis. , 2002, Angewandte Chemie.

[9]  Fyaz M. D. Ismail.  Important fluorinated drugs in experimental and clinical use , 2002 .

[10]  Eric Therrien,et al.  Targeting thrombin and factor VIIa: design, synthesis, and inhibitory activity of functionally relevant indolizidinones. , 2002, Bioorganic & medicinal chemistry letters.

[11]  Jeremy C. Smith,et al.  Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal‐gas entropy correction? , 2002, J. Comput. Chem..

[12]  A. Beatty,et al.  Solution and solid-state models of peptide CH...O hydrogen bonds. , 2002, Journal of the American Chemical Society.

[13]  A. D. Rodrigues,et al.  3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. , 2002, Journal of medicinal chemistry.

[14]  Gautam R Desiraju,et al.  Hydrogen bridges in crystal engineering: interactions without borders. , 2002, Accounts of chemical research.

[15]  F. Diederich,et al.  Structure‐Based Design of Nonpeptidic Thrombin Inhibitors: Exploring the D‐Pocket and the Oxyanion Hole , 2002 .

[16]  J. Engels,et al.  C-F...H-C hydrogen bonds in ribonucleic acids. , 2002, Journal of the American Chemical Society.

[17]  P. Winocour,et al.  Novel bicyclic lactam inhibitors of thrombin: highly potent and selective inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[18]  H. Nar,et al.  Structure-based design of novel potent nonpeptide thrombin inhibitors. , 2002, Journal of medicinal chemistry.

[19]  M. A. Carrondo,et al.  Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor (ARccr) Derived from an Androgen-Independent Prostate Cancer , 2002 .

[20]  T. Steiner.  The hydrogen bond in the solid state. , 2002, Angewandte Chemie.

[21]  R. B. Alencastro,et al.  Thermodynamic Analysis of Thrombin Inhibition by Benzamidine and p-Methylbenzamidine via Free-Energy Perturbations: Inspection of Intraperturbed-Group Contributions Using the Finite Difference Thermodynamic Integration (FDTI) Algorithm , 2002 .

[22]  J. Janc,et al.  Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets. , 2002, Chemistry & biology.

[23]  M. Witmer,et al.  2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies. , 2001, Organic letters.

[24]  M. Shiro,et al.  A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system. , 2001, Chemical communications.

[25]  Bruce E. Smart,et al.  Fluorine substituent effects (on bioactivity) , 2001 .

[26]  R Talhout,et al.  Thermodynamic analysis of binding of p-substituted benzamidines to trypsin. , 2001, European journal of biochemistry.

[27]  J. Huff,et al.  Conformational restriction of flexible ligands guided by the transferred noe experiment: potent macrocyclic inhibitors of farnesyltransferase. , 2001, Journal of the American Chemical Society.

[28]  E. Corey,et al.  The formyl C–H⋯O hydrogen bond as a critical factor in enantioselective Lewis-acid catalyzed reactions of aldehydes , 2001 .

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

[30]  C. Crudden,et al.  A Demonstration of the Primary Stereoelectronic Effect in the Baeyer–Villiger Oxidation ofα-Fluorocyclohexanones , 2000 .

[31]  F. Diederich,et al.  Synthesis of Novel Nonpeptidic Thrombin Inhibitors , 2000 .

[32]  Peter A. Kollman,et al.  A Ligand That Is Predicted to Bind Better to Avidin than Biotin: Insights from Computational Fluorine Scanning , 2000 .

[33]  B. Katz,et al.  Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator. , 2000, Chemistry & biology.

[34]  F. Diederich,et al.  Cleft‐Type Diamidinium Receptors for Dicarboxylate Binding in Protic Solvents , 2000 .

[35]  J. Snyder,et al.  The Unexpected Diaxial Orientation of cis-3,5-Difluoropiperidine in Water: A Potent CF- - -NH Charge-Dipole Effect , 2000 .

[36]  J. Rewinkel,et al.  Strategies and progress towards the ideal orally active thrombin inhibitor. , 1999, Current pharmaceutical design.

[37]  J. Doyon,et al.  Models of F.H contacts relevant to the binding of fluoroaromatic inhibitors to carbonic anhydrase II. , 1999, Organic letters.

[38]  Susie M. Miller,et al.  SIGNIFICANT INTER- AND INTRAMOLECULAR O-H...FC HYDROGEN BONDING , 1999 .

[39]  G. Desiraju,et al.  C−H···F Interactions in the Crystal Structures of Some Fluorobenzenes , 1998 .

[40]  S. Brady,et al.  Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. , 1998, Journal of medicinal chemistry.

[41]  Jonathan W. Essex,et al.  Monte Carlo Simulations for Proteins: Binding Affinities for Trypsin−Benzamidine Complexes via Free-Energy Perturbations , 1997 .

[42]  W. DeGrado,et al.  Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. , 1997, Journal of medicinal chemistry.

[43]  D W Banner,et al.  Molecular recognition at the thrombin active site: structure-based design and synthesis of potent and selective thrombin inhibitors and the X-ray crystal structures of two thrombin-inhibitor complexes. , 1997, Chemistry & biology.

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

[45]  Some influences of fluorine in bioorganic chemistry , 1997 .

[46]  B. Judkins,et al.  A versatile synthesis of amidines from nitriles via amidoximes , 1996 .

[47]  J. Howard,et al.  How good is fluorine as a hydrogen bond acceptor , 1996 .

[48]  F. Diederich,et al.  Design of Novel, Nonpeptidic Thrombin Inhibitors and Structure of a Thrombin–Inhibitor Complex , 1995 .

[49]  Paul R. Gerber,et al.  MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry , 1995, J. Comput. Aided Mol. Des..

[50]  L. Borges,et al.  On the Preparation of Aryl Nitriles Using Tosyl Cyanide , 1995 .

[51]  K Gubernator,et al.  Design and synthesis of potent and highly selective thrombin inhibitors. , 1994, Journal of medicinal chemistry.

[52]  Maria Cristina Burla,et al.  SIR92 – a program for automatic solution of crystal structures by direct methods , 1994 .

[53]  A. Bridges,et al.  Fluorine as an ortho-directing group in aromatic metalation: A two step preparation of substituted benzo[b]thiophene-2-carboxylates , 1992 .

[54]  S. Kanemasa,et al.  Recent Advances in Azomethine Ylide Chemistry , 1989 .

[55]  R. Grigg,et al.  The decarboxylative route to azomethine ylides. Mechanism of 1,3-dipole formation , 1987 .

[56]  J. Andrew McCammon,et al.  Dynamics and design of enzymes and inhibitors , 1986 .

[57]  R. Langridge,et al.  Quantitative structure-activity relationships and molecular graphics in ligand receptor interactions: amidine inhibition of trypsin. , 1986, Molecular pharmacology.

[58]  G. Náray‐Szabó.  QUANTUM CHEMICAL CALCULATION OF THE ENZYME-LIGAND INTERACTION ENERGY FOR TRYPSIN INHIBITION BY BENZAMIDINES. , 1984 .

[59]  D L Nelson,et al.  Electronic effects in the interaction of para-substituted benzamidines with trypsin: the involvement of the pi-electronic density at the central atom of the substituent in binding. , 1977, Journal of the American Chemical Society.

[60]  C. Weeks,et al.  A comparison of the molecular structures of six corticosteroids. , 1973, Journal of the American Chemical Society.

[61]  E. F. Sabo,et al.  9α-FLUORO DERIVATIVES OF CORTISONE AND HYDROCORTISONE , 1954 .