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1.  Design, Synthesis, and Characterization of α-Ketoheterocycles Additionally Targeting the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2014;57(3):1079-1089.
A series of α-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH), additionally targeting the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and non-competitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice with peak levels achieved within 1.5–3 h and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain inhibiting FAAH for a sustained period.
doi:10.1021/jm401820q
PMCID: PMC3940414  PMID: 24456116
2.  Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase 
Journal of Medicinal Chemistry  2014;57(3):1079-1089.
A series of α-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH) that additionally target the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and noncompetitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice, with peak levels achieved within 1.5–3 h, and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain, inhibiting FAAH for a sustained period.
doi:10.1021/jm401820q
PMCID: PMC3940414  PMID: 24456116
3.  A Fundamental Relationship Between Hydrophobic Properties and Biological Activity for the Duocarmycin Class of DNA Alkylating Antitumor Drugs: Hydrophobic Binding-Driven-Bonding 
Journal of medicinal chemistry  2013;56(17):6845-6857.
Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA are described that feature the incorporation of ethylene glycol units (n = 1–5) into the methoxy substituents of the trimethoxyindole subunit. These derivatives exhibit progressively increasing water solubility, along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. A linear relationship between cLogP and –logIC50 for cell growth inhibition and –logAE (AE = cell free DNA alkylation efficiency) is observed where cLogP values span the productive range of 2.5–0.49 and –logIC50 values span the range of 11.2–6.4, representing IC50 values covering a 105 range (0.008 to 370 nM). The results quantify a fundamental role the compound hydrophobic character plays in the expression of the biological activity of members in this class, driving the intrinsically reversible DNA alkylation reaction, and define the stunning magnitude of its effect.
doi:10.1021/jm400665c
PMCID: PMC3793852  PMID: 23944748
4.  Probing the Role of the Vancomycin E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues 
Journal of medicinal chemistry  2013;56(10):4116-4124.
The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid, and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively non-polar substituents approach or match the chloro substituted vancomycin and was insensitive to the electronic character of the substituent (e.g. Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon), and provides a direct method for the preparation of previously inaccessible analogues.
doi:10.1021/jm4004494
PMCID: PMC3667592  PMID: 23617725
5.  Efficacious Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrugs 
Journal of medicinal chemistry  2013;56(10):4104-4115.
Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors) substantially exceeding that of the free drug, that its therapeutic window of activity is much larger permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.
doi:10.1021/jm400413r
PMCID: PMC3687800  PMID: 23627265
6.  A Remarkable Series of Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented Tubulin Binding Steric Tolerance: C20' Urea Derivatives 
Journal of medicinal chemistry  2012;56(3):628-639.
A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH4-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an x-ray co-crystal structure, remarkably large C20' urea derivatives are accommodated.
doi:10.1021/jm3015684
PMCID: PMC3574233  PMID: 23244701
7.  Total Synthesis and Evaluation of Vinblastine Analogues Containing Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign 
Journal of medicinal chemistry  2013;56(2):483-495.
The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6 and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.
doi:10.1021/jm3014376
PMCID: PMC3554876  PMID: 23252481
8.  A Novel, Unusually Efficacious Duocarmycin Carbamate Prodrug That Releases No Residual Byproduct 
Journal of Medicinal Chemistry  2012;55(12):5878-5886.
A unique heterocyclic carbamate prodrug of seco-CBI-indole2 that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.
doi:10.1021/jm300330b
PMCID: PMC3386426  PMID: 22650244
9.  Reversible Competitive α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Constraints in the Acyl Side Chain: Orally Active, Long Acting Analgesics 
Journal of medicinal chemistry  2011;54(8):2805-2822.
A series of α-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the -ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (i.p.) or oral (p.o.) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5–3 h and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (>6 h) and cold (>9 h) allodynia for sustained periods consistent with its long acting effects in raising the endogenous concentration of anandamide.
doi:10.1021/jm101597x
PMCID: PMC3085948  PMID: 21428410
10.  Design, Synthesis, and Evaluation of Duocarmycin O-Amino Phenol Prodrugs Subject to Tunable Reductive Activation 
Journal of medicinal chemistry  2010;53(21):7731-7738.
A series of N-acyl O-amino derivatives of seco-CBI-indole2 are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments, which carry an intrinsically higher concentration of “reducing” nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N–O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs even enlisting subtle variations in the electronic and steric environment around the weak N–O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.
doi:10.1021/jm1010397
PMCID: PMC2974002  PMID: 20942408
11.  Synthesis and Evaluation of Selected Key Methyl Ether Derivatives of Vancomycin Aglycon 
Journal of medicinal chemistry  2010;53(19):7229-7235.
A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis, as well as their binding affinity for D-Ala-D-Ala and D-Ala-D-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B-, and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site-directed modification of the vancomycin aglycon core.
doi:10.1021/jm100946e
PMCID: PMC2981068  PMID: 20853900
12.  X-ray Crystallographic Analysis of α-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2010;53(1):230-240.
Three cocrystal X-ray structures of the α-ketoheterocycle inhibitors 3–5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the α-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure–activity relationships are discussed providing important insights for future design.
doi:10.1021/jm9012196
PMCID: PMC2804032  PMID: 19924997
14.  Synthesis and Evaluation of Vancomycin Aglycon Analogues that Bear Modifications in the N-terminal d-Leucyl Amino Acid 
Journal of medicinal chemistry  2009;52(5):1471-1476.
The synthesiys and biological evaluation of a series of vancomycin aglycon analogues bearing alternate residue 1 N-methyl-d-amino acids are described. The analogues were prepared to define whether H-bonding d-amino acids could improve the affinity for the model ligands N,N′-Ac2-l-Lys-d-Ala-d-Ala (2) and N,N′-Ac2-l-Lys-d-Ala-d-Lac (3), and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophiles (hydrazines and amines) on the residue 1 d-amino acids are described that were examined for their ability to react with the C-terminal ester of 3, forming a covalent attachment of l-Lys-d-Ala to the natural product analogues.
doi:10.1021/jm801549b
PMCID: PMC2765482  PMID: 19209892
15.  Asymmetric Synthesis of Inhibitors of Glycinamide Ribonucleotide Transformylase 
Journal of medicinal chemistry  2008;51(17):5441-5448.
Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors and has emerged as a productive target for antineoplastic therapeutic intervention. The asymmetric synthesis and evaluation of the two diastereomers of 10-methylthio-DDACTHF (10R-3 and 10S-3) and related analogues as potential inhibitors of GAR Tfase are reported. This work, which defines the importance of the C10 stereochemistry for this class of inhibitors of GAR Tfase, revealed that both diastereomers are potent inhibitors of rhGAR Tfase (10R-3 Ki = 210 nM, 10S-3 Ki = 180 nM) that exhibit effective cell growth inhibition (CCRF-CEM IC50 = 80 and 50 nM, respectively) which is dependent on intracellular polyglutamation by folylpolyglutamate synthetase (FPGS), but not intracellular transport by the reduced folate carrier.
doi:10.1021/jm800555h
PMCID: PMC2559975  PMID: 18686942
16.  Optimization of α-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2008;51(4):937-947.
A series of α-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents was prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6: Ki = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between −log Ki and Hammett σp of a magnitude (ρ = 2.7–3.0) that indicates the substituent electronic effect dominates confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle, but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improve FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.
doi:10.1021/jm701210y
PMCID: PMC2734917  PMID: 18247553
17.  Optimization of the Central Heterocycle of α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2008;51(15):4392-4403.
The synthesis and evaluation of a refined series of α-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity: 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
doi:10.1021/jm800136b
PMCID: PMC2556205  PMID: 18630870
18.  Discovery of a Potent, Nonpolyglutamatable Inhibitor of Glycinamide Ribonucleotide Transformylase 
Journal of medicinal chemistry  2006;49(10):2998-3002.
Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors. Herein we report the discovery of a potent, non-polyglutamatable, and selective inhibitor of GAR Tfase. Compound 12, which possesses a tetrazole in place of the γ-carboxylic acid in the l-glutamate subunit of the potent GAR Tfase inhibitor 1, was active in cellular-based functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 40 nM, CCRF–CEM) and was selective for inhibition of rhGAR Tfase (Ki = 130 nM). Notably, 12 was only 2.5-fold less potent than 1 in cellular assays and 4-fold less potent against rhGAR Tfase. Like 1, this functional activity of 12 in the cell-based assay benefits from and requires transport into the cell by the reduced folate carrier but, unlike 1, is independent of folyl polyglutamate synthase (FPGS) expression levels and polyglutamation.
doi:10.1021/jm0601147
PMCID: PMC2531195  PMID: 16686541
19.  Structure–Activity Relationships of α-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2007;50(14):3359-3368.
A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
doi:10.1021/jm061414r
PMCID: PMC2531194  PMID: 17559203
20.  Potent and Selective α-Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolase 
Journal of medicinal chemistry  2007;50(5):1058-1068.
A study of the structure–activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12–14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, non-aromatic C5-substituents was also explored and revealed that the Ki follows a well-defined correlation with the Hammett σp constant (ρ = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency leading to inhibitors with Ki’s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
doi:10.1021/jm0611509
PMCID: PMC2531193  PMID: 17279740
21.  Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesicsa 
Journal of medicinal chemistry  2005;48(6):1849-1856.
Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against all serine hydrolases ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
doi:10.1021/jm049614v
PMCID: PMC2492884  PMID: 15771430

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