Journal of Medicinal Chemistry

Journal: Journal of Medicinal Chemistry

Abbreviation

J. Med. Chem.

Publisher

American Chemical Society

ISSN

1520-4804
0022-2623

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Publications1 - 10 of 78

Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors
Haider, Ahmed; Gobbi, Luca; Kretz, Julian; et al. (2020)
Journal of Medicinal Chemistry
Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]RoSMA-18-d6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation. © 2020 American Chemical Society.
Synthesis and biological evaluation of iodinated and fluorinated 9-(2-hydroxypropyl) and 9-(2-hydroxyethoxy)methyl purine nucleoside analogues
Svjetlana Prekupec, Silvana; Svedružić, Draženka; Gazivoda, Tatjana; et al. (2003)
Journal of Medicinal Chemistry
Structure-Activity Relationship in Pyrazolo[4,3-c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity
Dawidowski, Maciej; Kalel, Vishal C.; Napolitano, Valeria; et al. (2020)
Journal of Medicinal Chemistry
Extending the Structure–Activity Relationship of Anthranilic Acid Derivatives As Farnesoid X Receptor Modulators
Merk, Daniel; Lamers, Christina; Ahmad, Khalil; et al. (2014)
Journal of Medicinal Chemistry
Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography
Taddio, Marco F.; Mu, Linjing; Castro Jaramillo, Claudia Adriana; et al. (2019)
Journal of Medicinal Chemistry
The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure–affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.
Toward the Optimization of Bombesin-Based Radiotracers for Tumor Targeting
Valverde, Ibai E.; Vomstein, Sandra; Mindt, Thomas L. (2016)
Journal of Medicinal Chemistry
Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking
Graaf, Chris de; Pospisil, Pavel; Pos, Wouter; et al. (2005)
Journal of Medicinal Chemistry
Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity
Grace, Christy Rani R.; Erchegyi, Judit; Samant, Manoj; et al. (2008)
Journal of Medicinal Chemistry
Structure-Activity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES 1)
Rörsch, Florian; Buscato, Estel la; Deckmann, Klaus; et al. (2012)
Journal of Medicinal Chemistry
Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations
Urgaonkar, Sameer; Nosol, Kamil; Said, Ahmed M.; et al. (2022)
Journal of Medicinal Chemistry
Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar hound to human P-gp. The structure guided us to prudently decorate the encequidar scaffold with CYP3A4 pharmacophores, leading to the identification of several analogues with dual potency against P-gp and CYP3A4. In vivo, dual P-gp and CYP3A4 inhibitor 3a improved the oral absorption of docetaxel by 3-fold as compared to vehicle, while 3a itself remained poorly absorbed.

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