- Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor
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Due to the biological complexity of the N-methyl-d-aspartate receptor (NMDAR), the development of a positron emission tomography radiotracer for the imaging of NMDAR has met with limited success. Recent studies have established the presence of GluN2A subunit of the NMDAR in the heart and its role in the regulation of intracellular calcium levels. In our efforts to develop an imaging agent for the GluN2A subunit, we designed three new compounds based on a quinoxaline scaffold. The synthesis of the analogues was based on a two-step Kabachnik–Fields reaction in sequence with Suzuki cross-coupling and acid hydrolysis. They exhibited comparable high binding affinity values below 5 nm. A two-step radiolabeling procedure was successfully developed for the synthesis of [18F]1. [18F]1 was obtained in a modest overall radiochemical yield of 5.5 ± 4.2%, a good specific radioactivity of 254 ± 158 GBq/μmol, and a radiochemical purity > 99%. While compounds 2 and 3 showed comparable binding affinity towards NMDAR, sluggish radiolabeling, prevented their further evaluation. For [18F]1, in vitro autoradiography on rat heart slices demonstrated heterogeneous but unspecific accumulation, whereas for the brain a high in vitro specificity towards NMDAR, could be demonstrated.
- Milicevic Sephton, Selena,Vetterli, Peter T.,Pedani, Valentina,Cermak, Stjepko,Chiotellis, Aristeidis,Roscales, Sylvia,Müller Herde, Adrienne,Schibli, Roger,Auberson, Yves P.,Ametamey, Simon M.
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Read Online
- Synthesis, in Vitro Evaluation, and Radiolabeling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis
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There is currently no ideal radiotracer for imaging of protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18-labeled amino acid-based radiotracers predominantly visualize amino acid transporter processes, and in many cases they are not incorporated into nascent proteins at all. Others are radiolabeled with the short-half-life positron emitter carbon-11, which is rather impractical for many PET centers. Based on the puromycin (6) structural manifold, a series of 10 novel derivatives of 6 was prepared via Williamson ether synthesis from a common intermediate. A bioluminescence assay was employed to study their inhibitory action on protein synthesis, which identified the fluoroethyl analogue 7b as a lead compound. The fluorine-18 analogue was prepared via nucleophilic substitution of the corresponding tosylate precursor in a modest radiochemical yield of 2 ± 0.6% with excellent radiochemical purity (>99%) and showed complete stability over 3 h at ambient temperature.
- Betts, Helen M.,Milicevic Sephton, Selena,Tong, Carmen,Awais, Ramla O.,Hill, Philip J.,Perkins, Alan C.,Aigbirhio, Franklin I.
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supporting information
p. 9422 - 9430
(2016/11/11)
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- Pharmacophore-based design of novel oxadiazoles as selective sphingosine-1-phosphate (S1P) receptor agonists with in vivo efficacy
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Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2′-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2′-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1-selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.
- Quattropani, Anna,Sauer, Wolfgang H. B.,Crosignani, Stefano,Dorbais, Jerome,Gerber, Patrick,Gonzalez, Jerome,Marin, Delphine,Muzerelle, Mathilde,Beltran, Fanny,Nichols, Anthony,Georgi, Katrin,Schneider, Manfred,Vitte, Pierre-Alain,Eligert, Valerie,Novo-Perez, Laurence,Hantson, Jennifer,Nock, Sebastien,Carboni, Susanna,De Souza, Adriano Luis Soares,Arrighi, Jean-Fran?ois,Boschert, Ursula,Bombrun, Agnes
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p. 688 - 714
(2015/04/14)
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- TRIAZOLE AND IMIDAZOLE DERIVATIVES FOR USE AS TGR5 AGONISTS IN THE TREATMENT OF DIABETES AND OBESITY
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The present invention comprises TGR5 agonists of structural formula I, wherein X, R1, R2, and R5 are defined herein, as well as N-oxides of them and pharmaceutically acceptable salts thereof. The invention further comprise
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Page/Page column 86
(2012/01/30)
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- Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells
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We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in th
- Ferrigno, Federica,Branca, Danila,Kinzel, Olaf,Lillini, Samuele,Llauger Bufi, Laura,Monteagudo, Edith,Muraglia, Ester,Rowley, Michael,Schultz-Fademrecht, Carsten,Toniatti, Carlo,Torrisi, Caterina,Jones, Philip
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scheme or table
p. 1100 - 1105
(2010/06/15)
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- Potassium channel openers
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Compounds having the formula I: are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.
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- Non-covalent thrombin inhibitors featuring P3-heterocycles with P1-bicyclic arginine surrogates
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Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa ~non-basic - 8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.
- Cui, Jingrong Jean,Araldi, Gian-Luca,Reiner, John E.,Reddy, Komandla Malla,Kemp, Scott J.,Ho, Jonathan Z.,Siev, Daniel V.,Mamedova, Lala,Gibson, Tony S.,Gaudette, John A.,Minami, Nathaniel K.,Anderson, Susanne M.,Bradbury, Annette E.,Nolan, Thomas G.,Semple
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p. 2925 - 2930
(2007/10/03)
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- Guanidine mimics as factor Xa inhibitors
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The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings D—E represent guanidine mimics, which are useful as inhibitors of factor Xa.
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Page column 93
(2010/02/04)
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- Aryloxy substituted N-arylpiperazinones as dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I
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A series of aryloxy substituted piperazinones with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to have potent inhibitory activity in vitro and are promising agents for the inhibition of
- Bergman, Jeffrey M,Abrams, Marc T,Davide, Joseph P,Greenberg, Ian B,Robinson, Ronald G,Buser, Carolyn A,Huber, Hans E,Koblan, Kenneth S,Kohl, Nancy E,Lobell, Robert B,Graham, Samuel L,Hartman, George D,Williams, Theresa M,Dinsmore, Christopher J
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p. 1411 - 1415
(2007/10/03)
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- Potassium channel openers
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Compounds having the formula are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.
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- Potent cyclic urea HIV protease inhibitors with 3-aminoindazole P2/P2' groups
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Cyclic ureas containing 3-aminoindazole P2/P2' groups are extremely potent inhibitors of HIV protease. The parent 3-aminoindazole 6 showed a K(i) 0.01 nM but poor translation of enzyme activity to antiviral activity was observed. A series of 3-alkylaminoindazoles revealed that translation improved with increasing lipophilicity. An X-ray crystal structure of 6 bound to HIV protease was obtained.
- Rodgers, James D.,Johnson, Barry L.,Wang, Haisheng,Erickson-Viitanen, Susan,Klabe, Ronald M.,Bacheler, Lee,Cordova, Beverly C.,Chang, Chong-Hwan
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p. 715 - 720
(2007/10/03)
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