Journal of Medicinal Chemistry

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  1. Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.

    Journal of Medicinal Chemistry (2016) PMID 27983835

    By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the seri...
  2. Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations.

    Journal of Medicinal Chemistry 51(12):3526 (2008) PMID 18512901

    Structure-activity relationships (SARs) of 1 (SR141716) have been extensively documented, however, the conformational properties of this class have received less attention. In an attempt to better understand ligand conformations optimal for receptor recognition, we have designed and synthesized ...
  3. Identification of MMP-12 inhibitors by using biosensor-based screening of a fragment library.

    Journal of Medicinal Chemistry 51(12):3449 (2008) PMID 18494455

    Small inhibitors of matrix metalloproteinase 12 (MMP-12) have been identified with a biosensor-based screening strategy and a specifically designed fragment library. The interaction between fragments and three variants of the target and a reference protein with an active-site zinc ion was measur...
  4. DNA interactions of monofunctional organometallic osmium(II) antitumor complexes in cell-free media.

    Journal of Medicinal Chemistry 51(12):3635 (2008) PMID 18494458

    This work is the first in-depth study of osmium binding to DNA and confirms the pharmacological activity of a new class of anticancer metallodrugs. We investigated the interactions between the potential biological target DNA and four osmium(II) arene complexes, of the type [(eta 6-arene)Os(LL)Cl...
  5. Homology modeling and site-directed mutagenesis to identify selective inhibitors of endothelin-converting enzyme-2.

    Journal of Medicinal Chemistry 51(12):3378 (2008) PMID 18507370 PMCID PMC2706147

    Endothelin-converting enzyme-2 (ECE-2), a member of M13 family of zinc metallopeptidases, has previously been shown to process a number of neuropeptides including those derived from prodynorphin, proenkephalin, proSAAS, and amyloid precursor protein. ECE-2, unlike ECE-1, exhibits restricted neur...
  6. 16-Cyclopentadienyl tricarbonyl 99mTc 16-oxo-hexadecanoic acid: synthesis and evaluation of fatty acid metabolism in mouse myocardium.

    Journal of Medicinal Chemistry 51(12):3630 (2008) PMID 18503263

    We synthesized 16-cyclopentadienyl tricarbonyl 99mTc 16-oxo-hexadecanoic acid (99mTc-CpTT-16-oxo-HDA, 1) and investigated its potential as a radiotracer for evaluating fatty acid metabolism in myocardium. Radiotracer 1 was synthesized in 22.6 +/- 6.3% decay-corrected yield by a double ligand tra...
  7. Synthesis and biological evaluation of D-amino acid oxidase inhibitors.

    Journal of Medicinal Chemistry 51(12):3357 (2008) PMID 18507366

    D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including d-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[ d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chloro-benzo[ d]isoxazol-3-ol (CBIO) p...
  8. Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa.

    Journal of Medicinal Chemistry 51(12):3583 (2008) PMID 18510371

    Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 ...
  9. Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit.

    Journal of Medicinal Chemistry 51(12):3353 (2008) PMID 18494460

    The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes. To gain insight into their mechanism of action, the crystal structure of the canonical oxazolidinone, linezolid, has been determined bound to the Haloarcula marismortui 50S subunit. Linezolid binds the 50S A-site, ...
  10. Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties of novel indeno[2,1-c]quinolin-7-one and indeno[1,2-c]isoquinolin-5,11-dione derivatives.

    Journal of Medicinal Chemistry 51(12):3617 (2008) PMID 18507368

    Indeno[2,1- c]quinolin-7-ones and 6 H-indeno[1,2- c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA an...
  11. Synthesis and in vitro antiprotozoal activities of water-soluble, inexpensive 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives.

    Journal of Medicinal Chemistry 51(12):3654 (2008) PMID 18476684

    3,7-Bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against Plasmodium falciparum, Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani. Notably, the compounds showed potent antiprotozoal activities, especially against P. falciparum and T....
  12. Designing selective, high affinity ligands of 5-HT1D receptor by covalent dimerization of 5-HT1F ligands derived from 4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide.

    Journal of Medicinal Chemistry 51(12):3609 (2008) PMID 18507369

    We demonstrate here that covalent dimerization of 5-HT 1 ligands is an effective design strategy to modulate affinity and selectivity of 5-HT 1 ligands. This approach was applied to LY-334370, a selective agonist of 5-HT 1F receptor, to generate structurally well-defined divalent molecules. Radi...
  13. Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy.

    Journal of Medicinal Chemistry 51(12):3572 (2008) PMID 18517259

    We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD...
  14. Protein-ligand docking accounting for receptor side chain and global flexibility in normal modes: evaluation on kinase inhibitor cross docking.

    Journal of Medicinal Chemistry 51(12):3499 (2008) PMID 18517186

    Efficient treatment of conformational changes during docking of drug-like ligands to receptor molecules is a major computational challenge. A new docking methodology has been developed that includes ligand flexibility and both global backbone flexibility and side chain flexibility of the protein...
  15. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum.

    Journal of Medicinal Chemistry 51(12):3649 (2008) PMID 18522386 PMCID PMC2624570

    A Plasmodium falciparum dihydroorotate dehydrogenase ( PfDHODH) inhibitor that is potent ( KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpen...
  16. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.

    Journal of Medicinal Chemistry 51(12):3588 (2008) PMID 18517184

    A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregat...
  17. Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkylcarbamates.

    Journal of Medicinal Chemistry 51(12):3487 (2008) PMID 18507372 PMCID PMC3744893

    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 ext...
  18. Discovery of imidazo[1,5-c]imidazol-3-ones: weakly basic, orally active factor Xa inhibitors.

    Journal of Medicinal Chemistry 51(12):3422 (2008) PMID 18507371

    The coagulation enzyme factor Xa (FXa) has been recognized as a promising target for the development of new antithrombotic agents. We previously found compound 1 to be an orally bioavailable FXa inhibitor in fasted monkeys; however, 1 showed poor bioavailability in rats and fed monkeys. To work ...
  19. Chemically induced dimerization of human nonpancreatic secretory phospholipase A2 by bis-indole derivatives.

    Journal of Medicinal Chemistry 51(12):3360 (2008) PMID 18522384

    A series of novel bis-indole compounds, 1,omega-bis(((3-acetamino-5-methoxy-2-methylindole)-2-methylene)phenoxy)alkane, have been designed and synthesized on the basis of the enzyme structure of human nonpancreatic secretory phospholipase A2 (hnps PLA2). Their inhibition activities against hnps ...
  20. CYP53A15 of Cochliobolus lunatus, a target for natural antifungal compounds.

    Journal of Medicinal Chemistry 51(12):3480 (2008) PMID 18505250

    A novel cytochrome P450, CYP53A15, was identified in the pathogenic filamentous ascomycete Cochliobolus lunatus. The protein, classified into the CYP53 family, was capable of para hydroxylation of benzoate. Benzoate is a key intermediate in the metabolism of aromatic compounds in fungi and yet b...