Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkylcarbamates.

Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure-activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (FAAH IC50 = 63 nM) with a selected set of substituents of different size, shape, flexibility, and lipophilicity. Docking experiments and linear interaction energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the beta-naphthylmethyl derivative 4q (IC50 = 5.3 nM) and its 3'-carbamoylbiphenyl-3-yl ester 4z (URB880, IC50 = 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors.

[1]  C. Fowler,et al.  The palmitoylethanolamide family: a new class of anti-inflammatory agents? , 2002, Current medicinal chemistry.

[2]  Chris Oostenbrink,et al.  Are Automated Molecular Dynamics Simulations and Binding Free Energy Calculations Realistic Tools in Lead Optimization? An Evaluation of the Linear Interaction Energy (LIE) Method , 2006, J. Chem. Inf. Model..

[3]  W. L. Jorgensen,et al.  Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations. , 2006, Journal of the American Chemical Society.

[4]  R. Mangieri,et al.  Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress , 2007, Biological Psychiatry.

[5]  Ruhong Zhou,et al.  New Linear Interaction Method for Binding Affinity Calculations Using a Continuum Solvent Model , 2001 .

[6]  A. Duranti,et al.  Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors. , 2003, Journal of medicinal chemistry.

[7]  Robert C. Malenka,et al.  Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models , 2007, Nature.

[8]  A. Duranti,et al.  The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice , 2007, Journal of Pharmacology and Experimental Therapeutics.

[9]  J. Aqvist,et al.  A new method for predicting binding affinity in computer-aided drug design. , 1994, Protein engineering.

[10]  R. Hanzlik,et al.  Effects of steric bulk and conformational rigidity on fatty acid omega hydroxylation by a cytochrome P450 4A1 fusion protein. , 1996, Archives of biochemistry and biophysics.

[11]  Daniele Piomelli,et al.  Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models , 2006, British journal of pharmacology.

[12]  V. Snieckus,et al.  Substitution of hydroxybiaryls via directed ortho-lithiation of N-silylated O-aryl N-isopropylcarbamates. , 2005, The Journal of organic chemistry.

[13]  C. Reynolds,et al.  Calculation of the binding affinity of beta-secretase inhibitors using the linear interaction energy method. , 2003, Journal of medicinal chemistry.

[14]  B. Cravatt,et al.  Proteins regulating the biosynthesis and inactivation of neuromodulatory fatty acid amides. , 2001, Vitamins and hormones.

[15]  Adrian J Mulholland,et al.  Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase. , 2007, Biophysical journal.

[16]  B. Cravatt,et al.  Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. , 2005, Chemistry & biology.

[17]  Daniele Piomelli,et al.  Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). , 2006, CNS drug reviews.

[18]  B. Cravatt,et al.  Structure and function of fatty acid amide hydrolase. , 2005, Annual review of biochemistry.

[19]  C. Fowler,et al.  The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. , 2005, Journal of medicinal chemistry.

[20]  M. Mor,et al.  Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling. , 2008, Chemical communications.

[21]  D. Piomelli,et al.  Control of pain initiation by endogenous cannabinoids , 1998, Nature.

[22]  Giovanni Piersanti,et al.  Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies. , 2004, Journal of medicinal chemistry.

[23]  Stefano Moro,et al.  In Silico Binding Free Energy Predictability by Using the Linear Interaction Energy (LIE) Method: Bromobenzimidazole CK2 Inhibitors as a Case Study , 2007, J. Chem. Inf. Model..

[24]  D. Gibson,et al.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor. , 1992, Science.

[25]  B. Cravatt,et al.  Evidence for Distinct Roles in Catalysis for Residues of the Serine-Serine-Lysine Catalytic Triad of Fatty Acid Amide Hydrolase* , 2003, Journal of Biological Chemistry.

[26]  A. Duranti,et al.  The fatty-acid amide hydrolase inhibitor URB597 does not affect triacylglycerol hydrolysis in rat tissues. , 2006, Pharmacological research.

[27]  B. Cravatt,et al.  Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. , 2003, Current opinion in chemical biology.

[28]  S. Wold,et al.  Statistical Validation of QSAR Results , 1995 .

[29]  T. Cassano,et al.  Correction for Gobbi et al., Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Scriba,et al.  Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. , 2006, Journal of medicinal chemistry.

[31]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[32]  D. Boger,et al.  Structure−Activity Relationships of α-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase , 2007 .

[33]  Benjamin F. Cravatt,et al.  Potent and Selective α-Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolase , 2007 .

[34]  C. Michaux,et al.  Fatty Acid Amide Hydrolase: From Characterization to Therapeutics , 2007, Chemistry & biodiversity.

[35]  Donald L. Hertzog.  Recent advances in the cannabinoids , 2004 .

[36]  A. Duranti,et al.  Synthesis and Structure–Activity Relationships of FAAH Inhibitors: Cyclohexylcarbamic Acid Biphenyl Esters with Chemical Modulation at the Proximal Phenyl Ring , 2006, ChemMedChem.

[37]  D. Boger,et al.  Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. , 2005, Journal of medicinal chemistry.

[38]  G. F. Woods,et al.  The reaction of beta-cyclohexanedione (dihydroresorcinol) and its ethyl enol ether with phenylmagnesium bromide. , 1948, Journal of the American Chemical Society.

[39]  A. Duranti,et al.  Application of 3D‐QSAR in the Rational Design of Receptor Ligands and Enzyme Inhibitors , 2005, Chemistry & biodiversity.

[40]  A. Petrauskas,et al.  ACD/Log P method description , 2000 .

[41]  D. Boger,et al.  Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors. , 2006, Journal of the American Chemical Society.

[42]  M. Cascio,et al.  New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain. , 2007, Journal of medicinal chemistry.

[43]  S. Gaetani,et al.  Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α , 2003, Nature.

[44]  W. L. Jorgensen,et al.  Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method. , 1997, Journal of medicinal chemistry.

[45]  Jeffrey J. Gray,et al.  Applying linear interaction energy method for rational design of noncompetitive allosteric inhibitors of the sarco- and endoplasmic reticulum calcium-ATPase. , 2005, Journal of medicinal chemistry.

[46]  Jennifer A. Geaga,et al.  URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices. , 2007, Chemistry & biology.

[47]  Marya Liimatta,et al.  Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. , 2007, Biochemistry.

[48]  Johannes C. Hermann,et al.  QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation. , 2005, Chemical communications.

[49]  R. Friesner,et al.  Generalized Born Model Based on a Surface Integral Formulation , 1998 .

[50]  S. Gaetani,et al.  An anorexic lipid mediator regulated by feeding , 2001, Nature.

[51]  T. Nevalainen,et al.  Design, synthesis, and in vitro evaluation of carbamate derivatives of 2-benzoxazolyl- and 2-benzothiazolyl-(3-hydroxyphenyl)-methanones as novel fatty acid amide hydrolase inhibitors. , 2007, Journal of medicinal chemistry.

[52]  C. Fowler,et al.  Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleamide. , 2001, Biochemical pharmacology.

[53]  R. Friesner,et al.  Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides† , 2001 .

[54]  Raymond C Stevens,et al.  Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling , 2002, Science.

[55]  J. Åqvist,et al.  The linear interaction energy method for predicting ligand binding free energies. , 2001, Combinatorial chemistry & high throughput screening.

[56]  W. L. Jorgensen,et al.  AN EXTENDED LINEAR RESPONSE METHOD FOR DETERMINING FREE ENERGIES OF HYDRATION , 1995 .

[57]  G. K. Kohn,et al.  Carbamate Insecticides, Some Structural Relationships of a Group of Simple Alkyl Phenyl N-Methylcarbamates to Anticholinesterase Activity , 1965 .

[58]  A. Duranti,et al.  Tandem mass spectrometric data-FAAH inhibitory activity relationships of some carbamic acid O-aryl esters. , 2004, Journal of mass spectrometry : JMS.