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1.  Structural Analogues of Smoothened Intracellular Loops as Potent Inhibitors of Hedgehog Pathway and Cancer Cell Growth 
Journal of medicinal chemistry  2007;50(18):4534-4538.
Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling.
doi:10.1021/jm0705657
PMCID: PMC3956439  PMID: 17685505
2.  Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors 
Journal of medicinal chemistry  2007;51(1):10.1021/jm701052u.
We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl}-l-glutamic acid 4 and 11 nonclassical analogues 5–15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,2-dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl l-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
doi:10.1021/jm701052u
PMCID: PMC3885252  PMID: 18072727
3.  Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2′ Ligands in Pseudosymmetric Dipeptide Isosteres 
Journal of medicinal chemistry  2007;50(18):10.1021/jm070284z.
A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2′ ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor–protease structures with the LPV–protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure–activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.
doi:10.1021/jm070284z
PMCID: PMC3862176  PMID: 17696512
4.  Discovery of Novel Antitumor Antimitotic Agents That Also Reverse Tumor Resistance1 
Journal of medicinal chemistry  2007;50(14):10.1021/jm070194u.
We have discovered a novel series of 7-benzyl-4-methyl-5-[(2-substituted phenyl)ethyl]-7H-pyrrolo[2,3-d]-pyrimidin-2-amines, which possess antimitotic and antitumor activities against antimitotic-sensitive as well as resistant tumor cells. These agents bind to a site on tubulin that is distinct from the colchicine, vinca alkaloid, and paclitaxel binding sites and some, in addition to their antitumor activity, remarkably also reverse tumor resistance to antimitotic agents mediated via the P-glycoprotein efflux pump. The compounds were synthesized from N-(7-benzyl-5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpro-panamide 11 or the corresponding 5-iodo analog 14 via Sonogashira couplings with appropriate iodobenzenes or phenylacetylene followed by reduction and deprotection to afford the target analogs. Sodium and liquid NH3 afforded the debenzylated analogs. The most potent analog 1 was one to three digit nanomolar against the growth of both sensitive and resistant tumor cells in culture. Compounds of this series are promising novel antimitotic agents that have the potential for treating both sensitive and resistant tumors.
doi:10.1021/jm070194u
PMCID: PMC3858178  PMID: 17567121
5.  Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates 
Journal of medicinal chemistry  2007;50(13):10.1021/jm070165j.
The classical antifolate N-{4-[(2,4-diamino-5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)sulfanyl]benzoyl}-l-glutamic acid (2) and 15 nonclassical analogues (3–17) were synthesized as potential dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. 5-Ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (20) served as the key intermediate to which various aryl thiols and a heteroaryl thiol were appended at the 6-position via an oxidative addition reaction. The classical analogue 2 was synthesized by coupling the benzoic acid derivative 18 with diethyl l-glutamate followed by saponification. The classical compound 2 was an excellent inhibitor of human DHFR (IC50 = 66 nM) as well as a two digit nanomolar (<100 nM) inhibitor of the growth of several tumor cells in culture. Some of the nonclassical analogues were potent and selective inhibitors of DHFR from two pathogens (Toxoplasma gondii and Mycobacterium avium) that cause opportunistic infections in patients with compromised immune systems.
doi:10.1021/jm070165j
PMCID: PMC3850752  PMID: 17552508
6.  Small Molecule Inhibitors of Integrin α2β1 
Journal of medicinal chemistry  2007;50(22):10.1021/jm070252b.
Interactions between the integrin, α2β1, and extracellular matrix (ECM), particularly collagen, play a pivotal role in platelet adhesion and thrombus formation. Platelets interact with collagen in the subendothelial matrix that is exposed by vascular damage. To evaluate the potential of α2β1 inhibitors for anticancer and antithrombotic applications, we have developed a series of small molecule inhibitors of this integrin based on a prolyl-2,3-diaminopropionic acid (DAP) scaffold using solid-phase parallel synthesis. A benzene-sulfonamide substituent at the N-terminus of the dipepetide and a benzyl urea at the DAP side chain resulted in tight and highly selective inhibition of α2β1-mediated adhesion of human platelets and other cells to collagen.
doi:10.1021/jm070252b
PMCID: PMC3828121  PMID: 17915848
7.  A bi-directional, iterative approach to the structural delineation of the functional “chemoprint” in GPR40 for agonist recognition 
Journal of medicinal chemistry  2007;50(13):2981-2989.
GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work we conducted a bi-directional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional “chemoprint” of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our experimentally supported model suggested that H137(4.56), R183(5.39), N244(6.55), and R258(7.35) are directly involved in interactions with the ligand. We have proposed a polarized NH - π interaction between H137(4.56) and GW9508 as one of the contributing forces leading to the high potency of GW9508. The modeling approach presented in this work provides a general strategy for the exploration of receptor-ligand interactions in GPCRs beginning prior to acquisition of experimental data.
doi:10.1021/jm0614782
PMCID: PMC3592210  PMID: 17552505
8.  Structure Activity Relationship of Uridine 5′-Diphosphoglucose (UDP-Glucose) Analogues as Agonists of the Human P2Y14 Receptor 
Journal of medicinal chemistry  2007;50(9):2030-2039.
UDP-glucose (UDPG) and derivatives are naturally-occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Gα-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 ± 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged resides and provides a fertile region for agonist modification.
doi:10.1021/jm061222w
PMCID: PMC3408610  PMID: 17407275
G protein-coupled receptor; nucleotides; pyrimidines; phospholipase C; carbohydrates; uracil
9.  Molecular Modeling of the Human P2Y2 Receptor and Design of a Selective Agonist, 2′-Amino-2′-deoxy-2-thio-UTP 
Journal of medicinal chemistry  2007;50(6):1166-1176.
A rhodopsin-based homology model of the nucleotide-activated human P2Y2 receptor, including loops, termini, and phospholipids, was optimized with Monte Carlo Multiple Minimum. Docked UTP formed a nucleobase π–π complex with conserved Phe3.32. Selectivity-enhancing 2′-amino-2′-deoxy substitution interacted through π-hydrogen bonding with aromatic Phe6.51 and Tyr3.33. A “sequential ligand composition” approach for docking the flexible dinucleotide agonist Up4U demonstrated a shift of conserved cationic Arg3.29 from the UTP γ position to δ position of Up4U and Up4ribose. Sysnthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2′-Amino and 2-thio modifications synergized to enhance potency and selectivity; compound 8 (8 nM EC50) was 300-fold P2Y2-selective versus P2Y4. 2′-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance potency through a predicted hydrophilic interaction, possibly because of destabilization of the receptor-favored (N)-ribose conformation. This detailed view of P2Y2 receptor recognition suggests mutations for model validation.
doi:10.1021/jm060903o
PMCID: PMC3404812  PMID: 17302398
G protein–coupled receptor; nucleotides; docking; phospholipase C; pyrimidines; homology modeling
10.  Structure-Activity Relationships of 2,N6,5′-Substituted Adenosine Derivatives with Potent Activity at the A2B Adenosine Receptor 
Journal of medicinal chemistry  2007;50(8):1810-1827.
2, N6, and/or 5′ substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-aralkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was found to be a potent agonist of the human A2BAR in both binding and cAMP assays. Simplification, altered connectivity and mimicking of the indole ring of 17 failed to maintain A2BAR potency. Introduction of N6-ethyl or N6-guanidino substitution, shown to favor A2BAR potency, failed to enhance potency in the 2-(3-(indolyl)ethyloxy)adenosine series. Indole 5″- or 6″-halo substitution was favored at the A2BAR, but a 5′-N-ethylcarboxyamide did not further enhance potency. 2-(3″-(6″-Bromoindolyl)ethyloxy)adenosine 28 displayed an A2BAR EC50 value (nM) of 128, i.e. more potent than the parent 17 (299) and similar to 5′-N-ethylcarboxamidoadenosine (140). 28 was a full agonist at A2B and A2AARs and a low efficacy partial agonist at A1 and A3ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A2BAR potency and selectivity.
doi:10.1021/jm061278q
PMCID: PMC3405160  PMID: 17378544
G protein-coupled receptor; nucleosides; adenylate cyclase; purines; receptor binding; indole
11.  Quick Assembly of 1,4-Diphenyltriazoles as Probes Targeting β-Amyloid Aggregates in Alzheimer’s Disease 
Journal of Medicinal Chemistry  2007;50(14):3380-3387.
Accumulation of β-amyloid aggregates (Aβ) in the brain is linked to the pathogenesis of Alzheimer’s disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Aβ aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to Aβ aggregates (Ki = 4–30 nM), were conveniently assembled by “click chemistry.” Two radioiodinated probes, [125I]10a and [125I]10b, and two radiofluorinated probes, [18F]17a and [18F]17b, exhibited moderate lipophilicities and showed excellent initial brain penetrations and fast washouts from the normal mouse brain. In vitro autoradiography of postmortem AD brain sections and homogenates showed that these triazoles were binding to Aβ plaques. Preliminary results strongly suggest that use of click chemistry, which led to a 1,4-diphenyltriazole-based core, is a highly convenient and flexible approach for assembling novel imaging agents for targeting Aβ aggregates in senile plaques in the living human brain.
doi:10.1021/jm070467l
PMCID: PMC3374157  PMID: 17569520
12.  Pharmacological Properties of Bivalent Ligands Containing Butorphan Linked to Nalbuphine, Naltrexone and Naloxone at μ, δ and κ Opioid Receptors 
Journal of Medicinal Chemistry  2007;50(9):2254-2258.
Investigation of bivalent ligands at μ, δ and κ opioid receptors is now focused on the preparation of ligands containing κ agonist and μ agonist/antagonist pharmacophores at one end joined by a linking chain containing the μ antagonists pharmacophores (naltrexone, naloxone or nalbuphine) at the other end. These ligands were evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors and their relative efficacy in the [35S]GTPγS assay.
Ligands 6-8 displayed better or the same affinity at κ and μ receptors compared to the monovalent ligands 1-5. Ligands 6-8 generally showed reduced affinity at δ receptor compared to the monovalent ligands 1-5. Functional assays showed that the ligand 6 was a κ agonist/antagonist and μ antagonist whereas ligands 7 and 8 were κ agonists and μ agonists/antagonists.
doi:10.1021/jm061327z
PMCID: PMC3357624  PMID: 17407276
13.  Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme† 
Journal of medicinal chemistry  2007;50(17):4003-4015.
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 μM, EC50 = 0.44 μM, and TC50 ≥ 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
doi:10.1021/jm060103d
PMCID: PMC3057568  PMID: 17663538
14.  Doxazolidine Induction of Apoptosis by a Topoisomerase II-independent Mechanism 
Journal of medicinal chemistry  2007;50(18):4493-4500.
The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. The IC50 for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA crosslinking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase II-dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells, but induces apoptosis 4-fold better than doxorubicin. The IC50 for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II-deficient derivative of HL-60 cells, is 1420-fold lower than the IC50 for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, Doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II-independent.
doi:10.1021/jm070569b
PMCID: PMC2919335  PMID: 17696516
Doxorubicin; Doxazolidine; Topoisomerase II; Virtual Crosslink; HL-60/MX2
15.  Total Synthesis and Absolute Configuration of Laurenditerpenol: A Hypoxia Inducible Factor-1 Activation Inhibitor 
Journal of medicinal chemistry  2007;50(25):6299-6302.
The absolute stereo structure of the natural product laurenditerpenol (1S, 6R, 7S, 10R, 11R, 14S, 15R) has been accomplished from eight plausible stereoisomers by its first asymmetric total synthesis in a highly convergent and flexible synthetic pathway. Six stereoisomers of laurenditerpenol were synthesized and evaluated for their biological activity.
doi:10.1021/jm7011062
PMCID: PMC2911032  PMID: 18004798
16.  Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist 
Journal of medicinal chemistry  2007;50(25):6428-6435.
Compound 1 (FTY720, Fingolimod) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the S1P1 receptor. Compound 1 also provides a template molecule for studying the molecular biology of S1P receptors and related enzymes (kinases and phosphatases). In this study, two conformationally constrained analogues of 1 (3a and 3c) were asymmetrically synthesized in high optical purity. In vitro assessment documented that both analogues are Sphk2 substrates, their phosphorylated species are potent S1P1 receptor agonists, and 3a-P is a potent S1P3 antagonist. After oral administration in mice, both compounds evoked lymphopenia, but their duration of action differed markedly.
doi:10.1021/jm7010172
PMCID: PMC2895489  PMID: 17994678
17.  Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors as Antimalarials 
Journal of medicinal chemistry  2007;50(19):4585-4605.
Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure–activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.
doi:10.1021/jm0703340
PMCID: PMC2894570  PMID: 17722901
18.  The Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties 
Journal of medicinal chemistry  2007;50(16):3795-3803.
The sponge derived polyketide macrolides fijianolides A (1) and B (2) (a.k.a. isolaulimalide and laulimalide) have taxol-like microtubule-stabilizing activity and the latter exhibits potent cytotoxicity. Insight on the biogeographical and phenotypic variations of Cacospongia mycofijiensis is presented that will enable future study of the biosynthetic pathway that produces the fijianolides. In addition to fijianolides A and B, six new fijianolides, D–I (7–12), were isolated, each with modifications to the C-20 side chain of the macrolide ring. Compounds 7–12 exhibited a range of in vitro activities against HCT-116 and MDA-MB-435 cell lines. Fijianolides 8 and 10 were shown to disrupt interphase and mitotic division but were less potent than 2. An in vivo evaluation of 2 using tumor-bearing SCID mice demonstrated significant inhibition of growth in HCT-116 tumors over 28 days.
doi:10.1021/jm070410z
PMCID: PMC2772109  PMID: 17622130
19.  Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease 
Journal of medicinal chemistry  2007;50(18):4509-4515.
The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold and 3-fold, respectively, for PRD30N, PRI50V, PRV82A and PRI84V relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor 1 was approximately threefold less potent. The high resolution (1.11–1.60 Å) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PRD30N and PRV82A showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PRI50V and PRI84V. Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.
doi:10.1021/jm070482q
PMCID: PMC2751596  PMID: 17696515
HIV-1; protease inhibitor; GRL-98065; crystal structure; enzyme kinetics; hydrogen bonds
20.  Highly Potent Triazole-Based Tubulin Polymerization Inhibitors 
Journal of medicinal chemistry  2007;50(4):749-754.
We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents.
doi:10.1021/jm061142s
PMCID: PMC2694353  PMID: 17249649
21.  Development of novel enkephalin analogues which have enhanced opioid activities at both μ and δ opioid receptors 
Journal of medicinal chemistry  2007;50(22):5528-5532.
Enkephalin analogues with an 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed μ and δ opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety showed very high binding affinities (0.4 nM) at μ and δ receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.
doi:10.1021/jm061465o
PMCID: PMC2678914  PMID: 17927164
22.  Bifunctional [2’,6’-Dimethyl-l-tyrosine1]Endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-/δ-Agonist Opioid Ligands 
Journal of medicinal chemistry  2007;50(12):2753-2766.
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2’,6’-dimethyl-l-tyrosine) analogues were synthesized containing alkylated Phe3 derivatives, 2’-monomethyl (2, 2’), 3’,5’- and 2’,6’-dimethyl (3, 3’, and 4’, respectively), 2’,4’,6’-trimethyl (6, 6’), 2’-ethyl-6’-methyl (7, 7’) and 2’-isopropyl-6’-methyl (8, 8’) groups or Dmt (5, 5’). They had the following characteristics: (i) [Xaa3]EM-2 analogues improved μ- and δ-opioid receptor affinities, the latter were inconsequential (Kiδ= 491–3,451 nM); (ii) [Dmt1,Xaa3]EM-2 analogues enhanced μ- and δ-opioid receptor affinities (Kiμ = 0.069–0.32 nM; Kiδ = 1.83–99.8 nM) and lacked interaction with κ-opioid receptors, and (iii) elevated μ-bioactivity (IC50 = 0.12–14.4 nM) and abolished δ-agonism (IC50 > 10 µM; 2’, 3’, 4’, 5’, 6’); however, 4’ and 6’ exhibited mixed μ-agonism/δ-antagonism (4’: IC50μ = 0.12, pA2 = 8.15; 6’: IC50μ = 0.21 nM, pA2 = 9.05), and 7’ was a dual μ-/δ -agonist (IC50μ = 0.17 nM; IC50δ = 0.51 nM). Alteration of EM-2 activity by Dmt1 and alkylated Phe3 residues retained μ-receptor bioactivity and formed dual μ-/δ -agonists and mixed μ-agonists/δ-antagonists.
doi:10.1021/jm061238m
PMCID: PMC2669435  PMID: 17497839
23.  Quantitative Conformationally Sampled Pharmacophore (CSP) for δ Opioid Ligands: Reevaluation of hydrophobic moieties essential for biological activity 
Journal of medicinal chemistry  2007;50(8):1799-1809.
Recent studies have indicated several therapeutic applications for δ opioid agonists and antagonists. To exploit the therapeutic potential of δ opioids developing a structural basis for the activity of ligands at the δ opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (Bernard et al., JACS, 125: 3103–3107, 2003) is extended here to obtain quantitative models of δ opioid ligand efficacy and affinity. Quantification is performed via overlap integrals of the conformational space sampled by ligands with respect to a reference compound. Iterative refinement of the CSP model identified hydrophobic groups other than the traditional phenylalanine residues as important for efficacy and affinity in DSLET and ICI 174,864. The obtained models for a structurally diverse set of peptidic and non-peptidic δ opioid ligands offer good predictions with R2 values > 0.9 and the predicted efficacy for a set of test compounds was consistent with the experimental value.
doi:10.1021/jm0612463
PMCID: PMC2631547  PMID: 17367120
24.  Small molecules block the polymerisation of Z α1-antitrypsin and increase the clearance of intracellular aggregates 
Journal of medicinal chemistry  2007;50(22):5357-5363.
The Z mutant of α1-antitrypsin (Glu342Lys) causes a domain-swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerisation for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modelling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerisation. The best antagonists were effective at ratios of compound to Z α1-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α1-antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α1-antitrypsin.
doi:10.1021/jm070687z
PMCID: PMC2631427  PMID: 17918823
hepatic inclusions; cirrhosis; serpinopathies; drug design; serpins
25.  Radiolabeled Phenethylguanidines 
Journal of medicinal chemistry  2007;50(9):2078-2088.
The norepinephrine transporter (NET) substrates [123I]meta-iodobenzylguanidine (MIBG) and [11C]meta-hydroxyephedrine (HED) are used as markers of cardiac sympathetic neurons and adrenergic tumors (pheochromocytoma, neuroblastoma). However, their rapid NET transport rates limit their ability to provide accurate measurements of cardiac nerve density. [11C]Phenethylguanidine ([11C]1a) and 12 analogs ([11C]1b-m) were synthesized and evaluated as radiotracers with improved kinetics for quantifying cardiac nerve density. In isolated rat hearts, neuronal uptake rates of [11C]1a-m ranged from 0.24 to 1.96 mL/min/g wet, and six compounds had extremely long neuronal retention times (clearance T1/2 > 20 hr) due to efficient vesicular storage. PET studies in nonhuman primates with [11C]1e, N-[11C]guanyl-meta-octopamine, which has a slow NET transport rate, showed improved myocardial kinetics compared to HED. Compound [11C]1c, [11C]para-hydroxyphenethylguandine, which has a rapid NET transport rate, avidly accumulated into rat pheochromocytoma xenograft tumors in mice. These encouraging findings demonstrate that radiolabeled phenethylguanidines deserve further investigation as radiotracers of cardiac sympathetic innervation and adrenergic tumors.
doi:10.1021/jm061398y
PMCID: PMC2625310  PMID: 17419605

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