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1.  Rational design of substituted diarylureas: a scaffold for binding to G-quadruplex motifs 
Journal of medicinal chemistry  2008;51(24):7751-7767.
The design and synthesis of a series of urea-based non-polycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents is described. Their interactions with quadruplexes have been examined by means of Fluorescent Resonance Energy Transfer melting, circular dichroism and surface plasmon resonance-based assays. These validate the design concept for such urea-based ligands and also show that they have significant selectivity for compared to duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure activity relationships. Preliminary biological studies using short-term cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.
PMCID: PMC3967098  PMID: 19053833
rational design; diarylureas; quadruplex DNA
2.  Use of the Nitrile Oxide Cycloaddition (NOC) Reaction for Molecular Probe Generation: A New Class of Enzyme Selective Histone Deacetylase Inhibitors (HDACIs) Showing Picomolar Activity at HDAC6 
Journal of medicinal chemistry  2008;51(15):4370-4373.
A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of ∼2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.
PMCID: PMC3913184  PMID: 18642892
3.  The Micelle-Associated 3D Structures of Boc-Y(SO3)-Nle-G-W-Nle-D-2-phenylethylester (JMV-180) and CCK-8(s) Share Conformational Elements of a Calculated CCK1 Receptor-Bound Model 
Journal of medicinal chemistry  2008;51(13):3742-3754.
JMV-180 (1) and CCK-8(s) are high affinity ligands at the CCK1 receptor that have similar and different actions via this receptor. Here we calculate the tertiary structure of 1 or CCK-8(s) in the presence of dodecylphosphocholine micelles at pH 5.0 and 35 °C from 2D 1H NMR data recorded at 600 MHz. The NMR derived 3D structures of 1 and CCK-8(s) share a common type I β-turn around residues Nle3/M3 and G4 and diverge from each other structurally at the N- and C-termini. The fluorescence and circular dichroism spectral properties of these peptides are consistent with their NMR derived structures. The structures determined in the presence of DPC micelles are compared to available models of 1 or CCK-8(s) bound to the CCK1 receptor. For CCK and 1, these comparisons show that DPC micelle associated structures duplicate some important aspects of the models calculated from cross-linking derived constraints at the CCK1 receptor.
PMCID: PMC3909998  PMID: 18540665
4.  Pharmacological Exploitation of the Peroxisome Proliferator-Activated Receptor γ Agonist Ciglitazone to Develop a Novel Class of Androgen Receptor-Ablative Agents 
Journal of medicinal chemistry  2008;51(7):2100-2107.
Based on our finding that the peroxisome proliferator-activated receptor (PPAR)γ agonist ciglitazone at high doses was able to mediate PPARγ-independent transcriptional repression of androgen receptor (AR) in a tumor cell-specific manner, we used Δ2CG, a PPARγ-inactive analogue of ciglitazone, to conduct lead optimization to develop a novel class of AR-ablative agents. Structure-activity analysis indicates a high degree of flexibility in realigning Δ2CG’s structural moieties without compromising potency in AR repression, as evidenced by the higher AR-ablative activity of the permuted isomer 9 [(Z)-5-(4-hydroxy-benzylidene)-3-(1-methyl-cyclohexylmethyl)-thiazolidine-2,4-dione]. Further modificiations of 9 gave rise to 12 [(Z)-5-(4-hydroxy-3-trifluoromethyl-benzylidene)-3-(1-methyl-cyclohexylmethyl)-thiazolidine-2,4-dione] which completely inhibited AR expression in LNCaP cells at low μM concentrations. This AR downregulation led to growth inhibition in LNCaP cells through apoptosis induction. Moreover, the role of AR repression in the antiproliferative effect of compound 12 was validated by the differential inhibition of cell viability between androgen-responsive and androgen-nonresponsive cells.
PMCID: PMC3901315  PMID: 18335975
5.  Potent Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors: Classical and Nonclassical 2-Amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine Antifolates 
Journal of medicinal chemistry  2008;51(18):5789-5797.
N-{4-[(2-Amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl}-L-glutamic acid (4) and nine nonclassical analogues 5–13 were synthesized as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was 2-amino-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (16), which was converted to the 5-bromo-substituted compound 17 followed by an Ullmann reaction to afford 5–13. The classical analogue 4 was synthesized by coupling the benzoic acid derivative 19 with diethyl l-glutamate and saponification. Compound 4 is the most potent dual inhibitor of human TS (IC50 = 40 nM) and human DHFR (IC50 = 20 nM) known to date. The nonclassical analogues 5–13 were moderately potent against human TS with IC50 values ranging from 0.11 to 4.6 µM. The 4-nitrophenyl analogue 7 was the most potent compound in the nonclassical series, demonstrating potent dual inhibitory activities against human TS and DHFR. This study indicated that the 5-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human TS-DHFR inhibitory activity.
PMCID: PMC3892769  PMID: 18800768
6.  N9-Substituted 2,4-Diaminoquinazolines: Synthesis and Biological Evaluation of Lipophilic Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase 
Journal of medicinal chemistry  2008;51(19):10.1021/jm800694g.
N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Reduction of commercially available 2,4-diamino-6-nitroquinazoline 14 with Raney nickel afforded 2,4,6-triaminoquinazoline 15. Reductive amination of 15 with the appropriate benzaldehydes or naphthaldehydes, followed by N9-alkylation, afforded the target compounds 5–13. In the 2,5-dimethoxybenzylamino substituted quinazoline analogues, replacement of the N9—CH3 group of 4 with the N9—C2H5 group of 8 resulted in a 9- and 8-fold increase in potency against pcDHFR and tgDHFR, respectively. The N9—C2H5 substituted compound 8 was highly potent, with IC50 values of 9.9 and 3.7 nM against pcDHFR and tgDHFR, respectively. N9-propyl and N9-cyclopropyl methyl substitutions did not afford further increases in potency. This study indicates that the N9-ethyl substitution is optimum for inhibitory activity against pcDHFR and tgDHFR for the 2,4-diaminoquinazolines. Selectivity was unaffected by N9 substitution.
PMCID: PMC3885247  PMID: 18771252
7.  The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents1a-e 
Journal of medicinal chemistry  2008;51(15):10.1021/jm800244v.
Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I2. The condensation of α-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues 3 and 4, the ester precursors were deprotected, coupled with diethyl-l-glutamate, and saponified. Compounds 3 (IC50 = 60 nM) and 4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI50 ≤ 10−7 M. Nonclassical 17 (IC50 = 58 nM) was a potent inhibitor of Toxoplasma gondii (T. gondii) DHFR with >500-fold selectivity over human DHFR. Analogue 17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.
PMCID: PMC3858179  PMID: 18605720
8.  Synthesis and QSAR of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates 
Journal of medicinal chemistry  2008;51(12):3487-3498.
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) (IC50, for FAAH = 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 β-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.
PMCID: PMC3744893  PMID: 18507372
9.  Discovery of novel agonists and antagonists of the free fatty acid receptor one (FFAR1) using virtual screening 
Journal of medicinal chemistry  2008;51(3):625-633.
The G protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on 2D-similarity, 3D-pharmacophore searches and docking studies, using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally-confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions, and provided important information on the role of specific amino acids in binding and activation of FFAR1.
PMCID: PMC3711565  PMID: 18193825
10.  Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) Inhibitors 
Journal of medicinal chemistry  2008;51(21):6642-6645.
The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compound 5 (SR-3677) had an IC50 of ~3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacology studies showed that 5 was efficacious in both, increasing ex vivo aqueous humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.
PMCID: PMC3708311  PMID: 18834107
11.  Bornyl- and Isobornyl-Δ8-tetrahydrocannabinols: A Novel Class of Cannabinergic Ligands 
Journal of medicinal chemistry  2008;51(20):6393-6399.
Structure-activity relationship studies of classical cannabinoid analogs have established that the C3 aliphatic side chain plays a pivotal role in determining cannabinergic potency. In earlier work we provided evidence for the presence of subsites within the CB1 and CB2 cannabinoid receptor binding domains that can accommodate bulky conformationally defined substituents at the C3 alkyl side chain pharmacophore of classical cannabinoids. We have now extended this work with the synthesis of a series of Δ8-THC analogs in which bornyl substituents are introduced at the C3 position. Our results indicate that for optimal interactions with both CB1 and CB2 receptors, the bornyl substituents need to be within close proximity of the tricyclic core of Δ8-THC and that the conformational space occupied by the C3 substituents influences CB1/CB2 receptor subtype selectivity.
PMCID: PMC3700413  PMID: 18826296
12.  Magnetically Aligned Bicelles to Study the Orientation of Lipophilic Ligands in Membrane Bilayers 
Journal of medicinal chemistry  2008;51(21):6793-6799.
Magnetically aligned bicelles were used as a model membrane to study the orientation and dynamic properties of two cannabinoids (Δ8-THC and Me-Δ8-THC) using 31P- and 2H-NMR. The uniform alignment of the bicelles allowed us to obtain well resolved deuterium spectra from a solution NMR spectrometer. The preferred orientations of Δ8-THC and Me-Δ8-THC were calculated based on the measurements of individual quadrupolar splittings. Our results agree with previous experiments using multilamellar membranes as well as with molecular dynamics simulation data described here. In conjunction with our earlier report using small and fast tumbling bicelles, the present work of well aligned bicelles shows that bicelle preparations can provide either pseudo-isotropic or anisotropic NMR spectra to study the conformation, orientation and dynamic properties of ligands in membrane bilayers. Such data are of critical value for understanding the interactions of lipophilic drug molecules with membrane proteins.
PMCID: PMC3694723  PMID: 18834109
13.  An X-ray Snapshot of the Mechanism of Inactivation of Human Neutrophil Elastase by 1, 2, 5 –Thiadiazolidin-3-one 1, 1 Dioxide Derivatives‡ 
Journal of medicinal chemistry  2008;51(7):2003-2008.
The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastaseα (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor (I) by the enzyme generates an N-sulfonyl imine functionality that is tethered to Ser195, in accordance with the postulated mechanism of action of this class of inhibitors. The identity of the HNE-N-sulfonyl imine species was further corroborated using electrospray ionization mass spectrometry.
PMCID: PMC3623276  PMID: 18318470
14.  Structure-Activity Relationships of Truncated D- and L-4′-Thioadenosine Derivatives as Species-Independent A3 Adenosine Receptor Antagonists1 
Journal of medicinal chemistry  2008;51(20):6609-6613.
Novel D- and L-4′-thioadenosine derivatives lacking the 4′-hydroxymethyl moiety were synthesized, starting from D-mannose and D-gulonic γ-lactone, respectively, as potent and selective species-independent A3 adenosine receptor (AR) antagonists. Among the novel 4′-truncated 2-H nucleosides tested, a N6-(3-chlorobenzyl) derivative 7c was the most potent at the human A3 AR (Ki = 1.5 nM), but a N6-(3-bromobenzyl) derivative 7d showed the optimal species-independent binding affinity.
PMCID: PMC3616494  PMID: 18811138
15.  Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors§ 
Journal of medicinal chemistry  2008;51(8):2447-2456.
A series of polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) were synthesized and evaluated as isoform-selective histone deacetylase (HDAC) inhibitors. These analogues contain a polyamine chain to increase affinity for chromatin and facilitate cellular import. Seven PAHAs inhibited HDAC >50% (1 µM), and two PABAs inhibited HDAC >50% (5 µM). Compound 17 increased acetylated α-tubulin in HCT116 colon tumor cells 253-fold but only modestly increased p21waf1 and acetylated histones 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21waf1 and acetylated histones 3 and 4 but caused dose-dependent increases in p21waf1 in combination with 0.1 µM 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 µM. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.
PMCID: PMC3556737  PMID: 18348516
16.  Histone Deacetylase Inhibitors through Click Chemistry 
Journal of medicinal chemistry  2008;51(23):7417-7427.
Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5g (NSC746457) was discovered that inhibited HDAC1 at an IC50 value of 104 ± 30 nM and proved quite potent in the cancer cell line screen with GI50 values ranging from 3.92 μM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach.
PMCID: PMC3441833  PMID: 19007204
HDAC; histone; deacetylase; click chemistry; inhibitor; synthesis
17.  Trifluoromethoxyl Substituted Phenylethylene Diamines as High Affinity σ Receptor Ligands with Potent Anti-Cocaine Actions 
Journal of Medicinal Chemistry  2008;51(11):3322-3325.
The phenylethylene diamines are a class of σ receptor ligands with excellent selectivity over other biological systems and with anti-cocaine actions that involve antagonism of σ1 receptors. In order to increase the potency of the aromatic methoxyl substituted analogues, trifluoromethoxyl groups were introduced to prevent metabolic demethylation. The para-substituted trifluoromethoxyl substituted analogues were shown to have increased σ receptor affinity and represent the most potent anti-cocaine phenylethylene diamines yet described.
PMCID: PMC3401596  PMID: 18461921
18.  Opioids and Efflux Transporters. Part 2: P-Glycoprotein Substrate Activity of 3- and 6-Substituted Morphine Analogs 
Journal of Medicinal Chemistry  2008;51(7):2316-2320.
Continuing our studies investigating opioids with reduced P-glycoprotein (P-gp) substrate activity, a series of known 3- and 6-hydroxy, -methoxy, and -desoxymorphine analogs was synthesized and analyzed for P-gp substrate activity and opioid binding affinity. 6-Desoxymorphine (7) showed high affinity for opioid receptors and did not induce P-gp-mediated ATP hydrolysis. Additionally, 7 demonstrated morphine-like antinociceptive potency in mice, indicating this compound as an ideal lead to further evaluate the role of P-gp in opioid analgesic tolerance development.
PMCID: PMC3401598  PMID: 18311899
19.  Synthesis and Evaluation of Technetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen (PSMA) 
Journal of Medicinal Chemistry  2008;51(15):4504-4517.
The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven 99mTc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. Ki values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [99mTc(CO)3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH2)4CH(CO2H)-NHCO-(CH2)6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 ± 4.0% injected dose per gram of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the ε amine of the urea lysine and the chelator.
PMCID: PMC3336105  PMID: 18637669
20.  Synthesis of Novel β-Lactone Inhibitors of Fatty Acid Synthase 
Journal of medicinal chemistry  2008;51(17):5285-5296.
Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a β-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the α- and β-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
PMCID: PMC3172131  PMID: 18710210
21.  Potent s-cis-Locked Bithiazole Correctors of ΔF508 Cystic Fibrosis Transmembrance Conductance Regulator Cellular Processing for Cystic Fibrosis Therapy⊥§ 
Journal of medicinal chemistry  2008;51(19):6044-6054.
N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein ΔF508-CFTR. Eight C4′-C5 C,C-bond-controlling bithiazole analogs of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4′-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenyl-amino)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide; 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the “s-cis locked” cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of ~450 nM.
PMCID: PMC3167067  PMID: 18788728
22.  Structure Based Development of Phenyl-imidazole-derived Inhibitors of Indoleamine 2,3-Dioxygenase 
Journal of medicinal chemistry  2008;51(16):4968-4977.
Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. With the goal of developing more potent IDO inhibitors, a systematic study of 4-phenyl-imidazole (4-PI) derivatives was undertaken. Computational docking experiments guided design and synthesis efforts with analogs of 4-PI. In particular, three interactions of 4-PI analogs with IDO were studied: the active site entrance, the interior of the active site and the heme iron binding. The three most potent inhibitors (1, 17 and 18) appear to exploit interactions with C129 and S167 in the interior of the active site. All three inhibitors are approximately ten-fold more potent than 4-PI. The study represents the first example of enzyme inhibitor development with the recently reported crystal structure of IDO and offers important lessons in the search for more potent inhibitors.
PMCID: PMC3159384  PMID: 18665584
23.  Structure–Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol 
Journal of medicinal chemistry  2008;51(19):6095-6109.
Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; Ki(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
PMCID: PMC3157365  PMID: 18774793
24.  Enantiomeric Propanolamines as selective N-Methyl-d-aspartate 2B Receptor Antagonists† 
Journal of medicinal chemistry  2008;51(18):5506-5521.
Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11–64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30–100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
PMCID: PMC3142473  PMID: 18800760
25.  Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 2. Antiproliferative and Antitubulin Activities of Pyrano[3,2-c]pyridones and Pyrano[3,2-c]quinolones 
Journal of medicinal chemistry  2008;51(8):2561-2570.
Pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.
PMCID: PMC3125133  PMID: 18361483

Results 1-25 (158)