Structure–Property Relationships of a Class of Carbamate‐Based Fatty Acid Amide Hydrolase (FAAH) Inhibitors: Chemical and Biological Stability

Vacondio, Federica; Silva, Claudia; Lodola, Alessio; Fioni, Alessandro; Rivara, Silvia; Duranti, Andrea; Tontini, Andrea; Sanchini, Silvano; Clapper, Jason R.; Piomelli, Daniele; Mor, Marco; Tarzia, Giorgio

doi:10.1002/cmdc.200900120

Cited by 41 publications

(32 citation statements)

References 57 publications

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“…URB694) belongs to a recently reported second generation of phenyl carbamate FAAH inhibitors with improved pharmacological characteristics, including higher brain penetration. [20,28] To demonstrate the utility of our method we synthesized [ 11 C]-16 in quantities and qualities suitable for animal imaging studies (Scheme 1). The position of the radiolabel at the carbonyl carbon is crucial for tagging FAAH with this class of inhibitor as this is the point of attachment to the enzyme with loss of the O-biaryl group.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Application of Isocyanates Radiolabeled with Carbon‐11

Wilson

García

Houle

et al. 2010

Chemistry A European J

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Carbon-11 labeled isocyanates are efficiently prepared by dehydration of [(11) C]carbamate salts, which in turn are easily formed from cyclotron-produced [(11) C]CO(2) and amines in the presence of a CO(2) fixation agent. The [(11) C]isocyanates are useful radiosynthons for the synthesis of a variety of [carbonyl-(11) C]-labeled asymmetrical ureas and carbamate esters. The method is well suited to incorporate any isotope of carbon, and is especially useful for positron emission tomography (PET) radiotracers for in vivo imaging. This is demonstrated by using the method to make [carbonyl-(11) C]-6-hydroxy-[1,1'-biphenyl]-3-yl cyclohexylcarbamate which is a novel radiotracer for PET imaging of fatty acid amide hydrolase.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Application of Isocyanates Radiolabeled with Carbon‐11

Wilson

García

Houle

et al. 2010

Chemistry A European J

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“…Among such inhibitors are various alkyl-and aryl-carbamates and ureas responsible for the mechanism-based inhibition of enzymes by formation of carbamyl enzymes. Among these enzymes are fatty acid amide hydrolase (34,42), monoacylglycerol lipase (25), acetyl cholinesterase (21), and Pseudomonas species lipase (22). In all of these cases the enzyme forms a covalent carbamyl enzyme via the active-site serine, including in some cases via a substituted piperidine carbamyl link (25) as is the case with NXL104.…”

Section: Vol 54 2010 Inactivation Of ␤-Lactamases By Nxl104 5135mentioning

confidence: 99%

Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor

Stachyra¹,

Péchereau²,

Bruneau³

et al. 2010

Antimicrob Agents Chemother

134

125

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NXL104 is a potent inhibitor of class A and C serine ␤-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 ␤-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 ␤-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k 2 ), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k 2 /K of 3.7 ؋ 10 5 M ؊1 s ؊1 for TEM-1 and 1 ؋ 10 4 M ؊1 s ؊1 for P99) and slow decarbamylation. Complete loss of ␤-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k 3 value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC 50 s) were evaluated on selected ␤-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C ␤-lactamases. IC 50 s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the ␤-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.

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“…12 Structure-activity relationship (SAR) studies showed that conjugated, electron-donor groups on the biphenyl scaffold of URB524 (which increase electron density around the carbamate carbon) are associated with enhanced carbamate stability both in alkaline buffer and in rat plasma. 13 Conversely, these groups do not affect FAAH inhibitor potency in vitro. 7 To understand this apparent discrepancy, we here apply a QM/MM approach to model the carbamoylation reaction of FAAH by the reference inhibitor URB524 (IC 50 = 25.6 nM) and by its p-OH (URB694, IC 50 = 30.0 nM) and p-NH 2 (URB618, IC 50 = 27.2 nM) derivatives (Fig.…”

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Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling

et al. 2011

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QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electrondonor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency.Carbamate-based compounds are widely used as covalent inhibitors of serine hydrolases of therapeutic interest, including fatty acid amide hydrolase (FAAH). 1 This enzyme is characterized by an uncommon Ser-Ser-Lys catalytic triad. It is the main enzyme responsible for the hydrolysis of the endocannabinoid anandamide. Despite its unusual catalytic mechanism, 2-4 FAAH is inhibited by classical serine hydrolase inhibitors, 1 and by O-biphenyl-3-yl carbamates, which are promising clinical candidates for the treatment of central nervous system and peripheral disorders. 5 These carbamate inhibitors, e.g. URB524 (Fig. 1), can be docked in two possible orientations (called orientations I and II) within the FAAH catalytic site. 6,7 Recently, hybrid quantum mechanical/molecular mechanics (QM/MM) modelling, 8 using the B3LYP/6-31G(d)//PM3-CHARMM22 potential, showed that the inhibitory process is energetically preferred in orientation II. 9 This orientation allows the catalytic nucleophile, Ser241, to efficiently attack the carbonyl group of URB524 (Fig. 2), yielding a carbamoylated enzyme. 10

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Structure–Property Relationships of a Class of Carbamate‐Based Fatty Acid Amide Hydrolase (FAAH) Inhibitors: Chemical and Biological Stability

Cited by 41 publications

References 57 publications

Synthesis and Application of Isocyanates Radiolabeled with Carbon‐11

Synthesis and Application of Isocyanates Radiolabeled with Carbon‐11

Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor

Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling

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