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1.  Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors 
Journal of Medicinal Chemistry  2014;57(20):8204-8223.
Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
PMCID: PMC4207546  PMID: 24901260
2.  Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis 
Journal of medicinal chemistry  2013;56(12):5115-5129.
Inhibition of GSK-3β has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3β resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3β inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3β inhibitors, in particular analogs 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube® behavioral assay and showed anxiolytic-like signatures following daily dose administration (50 mg/kg, i.p.) for 13 days. Taken together, these results support the hypothesis that GSK-3β inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo.
PMCID: PMC3777810  PMID: 23725591
kinase inhibitor; GSK-3; maleimides; steroidogenesis; lithium; anxiolytic
3.  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
4.  An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity 
Journal of medicinal chemistry  2012;56(1):254-263.
Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology. We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report). The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism. In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analog of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity. This compound, 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1. Like compound 1, compound 7a specifically inhibits HR repair in human cells.
PMCID: PMC3619390  PMID: 23231413
DNA repair; Homologous recombination; RAD51; medicinal chemistry; structure activity relationship
5.  Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2- Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II 
Journal of medicinal chemistry  2013;56(13):10.1021/jm400510u.
A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds 24, 26, and 30 demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.
PMCID: PMC3843973  PMID: 23734673
6.  Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II 
Journal of medicinal chemistry  2012;55(22):9998-10009.
In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [3H]epibatidine binding studies together with functional assays based on 86Rb+ ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity, but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.
PMCID: PMC3532055  PMID: 23092294
7.  Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth 
Journal of medicinal chemistry  2012;55(22):9891-9899.
The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet non-selective inhibitor. Structure activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ~600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6 selective inhibitors that possess antiproliferative effects against melanoma cells.
PMCID: PMC3562128  PMID: 23009203
8.  Insights into the Structural Determinants Required for High Affinity Binding of Chiral Cyclopropane-Containing Ligands to α4β2-Nicotinic Acetylcholine Receptors; An Integrated Approach to Behaviorally Active Nicotinic Ligands 
Journal of medicinal chemistry  2012;55(18):8028-8037.
Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a co-crystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing, selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine our previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. In order to validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogs of compound 5. The most promising compound 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral endpoints in the rodent studies.
PMCID: PMC3464052  PMID: 22928944
9.  Synthesis, Biological Evaluation and Structure-Activity Relationships of N-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania 
Journal of Medicinal Chemistry  2012;55(7):3088-3100.
In our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against T. gondii tachyzoites with activity discovered for N-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against T. gondii as described elsewhere.1 Synthesis of a compound set was guided by T. gondii SAR with 1r found to be superior for T. gondii, also active against Thai and Sierra Leone strains of P. falciparum, and with superior ADMET properties as described elsewhere.1 Herein, synthesis methods and details of the chemical analysis of the compounds in this series are described. Further, this series of N-benzoyl-2-hydroxybenzamides was re-purposed for testing against four other protozoan parasites: T. b. rhodesiense, T. cruzi, L. donovani, and P. falciparum (K1 isolate). Structure-activity analyses led to the identification of compounds in this set with excellent anti-leishmanial activity (compound 1d). Overall, compound 1r was the best and had activity 21-fold superior to that of the standard anti-malarial drug chloroquine against the K1 P. falciparum isolate.
PMCID: PMC3330251  PMID: 22352841
10.  Identification of Novel α4β2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity 
Journal of Medicinal Chemistry  2012;55(2):812-823.
There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.
PMCID: PMC3272775  PMID: 22148173
11.  Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile 
Journal of Medicinal Chemistry  2012;55(2):717-724.
Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.
PMCID: PMC3292870  PMID: 22171543
12.  Discovery of Isoxazole Analogs of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression 
Journal of medicinal chemistry  2011;54(20):7280-7288.
Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.
PMCID: PMC3197876  PMID: 21905669
13.  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
14.  Chemistry and Pharmacological Characterization of Novel Nitrogen Analogs of AMOP-H-OH (Sazetidine-A; 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists 
Journal of medicinal chemistry  2010;53(19):6973-6985.
In order to advance therapeutic applications of nicotinic ligands, continuing research efforts are being directed toward the identification and characterization of novel nicotinic acetylcholine receptor (nAChR) ligands that are both potent and subtype selective. Herein we report the synthesis and pharmacological evaluation of members of a new series of 3-alkoxy-5-aminopyridine derivatives that display good selectivity for the α4β2-nAChR subtype based on ligand binding and functional evaluations. The most potent ligand in this series, compound 64, showed high radioligand binding affinity and selectivity for rat α4β2-nAChR with a Ki value of 1.2 nM and 4700-fold selectivity for α4β2-over α3β4-nAChR, and ~100-fold selectivity for functional, high-sensitivity, human α4β2-nAChR over α3β4*-nAChR. In the mouse forced swim test, compound 64 exhibited antidepressant-like effects. Structure-activity relationship (SAR) analyses suggest that the introduction of additional substituents to the amino group present on the pyridine ring of the N-demethylated analogue of compound 17 can provide potent α4β2-nAChR-selective ligands for possible use in treatment of neurological and psychiatric disorders including depression.
PMCID: PMC2957884  PMID: 20822184
15.  Identification and Development of Novel Inhibitors of Toxoplasma gondii Enoyl Reductase 
Journal of medicinal chemistry  2010;53(17):6287-6300.
Toxoplasmosis causes significant morbidity and mortality and yet available medicines are limited by toxicities and hypersensitivity. Since improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have anti-parasite MIC90s ≤6μM without toxicity to host cells, three compounds have IC90s <45nM against recombinant TgENR and two protect mice. To further understand the mode of inhibition, the co-crystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7Å. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
PMCID: PMC2932859  PMID: 20698542
16.  Synthesis and Biological Evaluation of Triazol-4-ylphenyl-Bearing Histone Deacetylase Inhibitors as Anticancer Agents 
Journal of medicinal chemistry  2010;53(3):1347-1356.
Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro, with the lowest IC50 value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogs by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogs was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC50 = 50 nM) and MiaPaca-2 (IC50 = 40 nM) cancer cell lines, respectively. Compound 4a was found to re-activate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
PMCID: PMC2919064  PMID: 20055418
17.  Selective 5-Hydroxytrytamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine – Identification of Drugs with Antidepressant-Like Action 
Journal of medicinal chemistry  2009;52(7):1885-1902.
We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37 with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10–60 mg/kg) decreased immobility time in the mouse forced swim test.
PMCID: PMC2832311  PMID: 19284718
18.  From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors that Suppress Proliferation and Survival of Pancreatic Cancer Cells 
Journal of medicinal chemistry  2009;52(7):1853-1863.
Recent studies have demonstrated that Glycogen Synthase Kinase 3β (GSK-3β) is overexpressed in human colon and pancreatic carcinomas contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl)maleimides, potent GSK-3β inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3β and an enhanced selectivity against Cyclin-dependent Kinase 2 (CDK-2). Selected GSK-3β inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20 and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3β inhibitors 5 and 26 resulted in suppression of GSK-3β activity and a distinct decrease of the X-linked Inhibitor of Apoptosis (XIAP) expression leading to significant apoptosis. The present data suggest a possible role for GSK-3β inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.
PMCID: PMC2665923  PMID: 19338355
19.  Synthesis and Pharmacological Evaluation of Novel 9- and 10- Substituted Cytisine Derivatives - Nicotinic Ligands of Enhanced Subtype Selectivity 
Journal of medicinal chemistry  2006;49(9):2673-2676.
We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the α4β2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
PMCID: PMC2504867  PMID: 16640326
20.  Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization 
Journal of medicinal chemistry  2004;47(24):5821-5824.
Some piperidine-based nocaine/modafinil hybrid ligands have been designed, synthesized, and found to display an improved potency at all three monoamine transporters and particularly for DAT and/or NET. Some highly active and selective monoamine transporter inhibitors with low nanomolar to subnanomolar potency were identified. Ligands of this type may find important applications as positron emission tomography imaging tools and in the treatment of central nervous system disorders such as depression and sleep apnea.
PMCID: PMC1395211  PMID: 15537337

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