161511-85-9Relevant articles and documents
Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors
Dolle, Frederic,Valette, Heric,Bottlaender, Michel,Hinnen, Francoise,Vaufrey, Francoise,Guenther, Ilonka,Crouzel, Christian
, p. 451 - 463 (1998)
This paper reports the synthesis of 2-fluoro-3-[2(S)-2- azetidinylmethoxy]pyridine and its radiolabeling with fluorine-18 ([18F]FK- K222) by nucleophilic aromatic nitro-to-fluoro substitution in DMSO by conventional heating at 150°C for 20 min or by microwave activation at 100 Watt for 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine). This compound is the lead compound of a novel 3-pyridyl ether series of new nAChR ligands recently published, and possesses not only subnanomolar comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes or nAChRs. 110-140 mCl (4.1-5.2 GBq) of pure 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) could be obtained in less than 2 hours, with specific radioactivities of 3-5 Ci/μmol (111-185 GBq/μmol) calculated for End of Bombardment (or 1.5-2.5 Ci/μmol (55.5-92.5 GBq/μmol) at End of Synthesis) for a 20 μA, 30 min (36000 μC) irradiation of a 95% enriched [18O]water target with a 16 MeV proton beam [18O(p,n)18F]. Yield (with respect to [18F]fluoride ion) : decay-corrected 49-64% ; non-decay corrected 25-33%. Total synthesis time from EOB : 105-110 min (this includes the recovery of the [18F]fluoride ion from the target and the [18F]FK-K222-complex preparation). Preliminary results in rats showed a substantial uptake of the ligand in the thalamus (1% I.D./g tissue at 30 min) while the cerebellar uptake was 2-fold lower. Thalamic uptake was reduced by 75-85% following a pre treatment with nicotine, cytisine, epibatidine or fluoro-A-85380. The full pharmacological profile and the potential for eventual clinical applications of this ligand as a tracer for PET experiments are currently under investigation.
Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase
Angst, Daniela,Gessier, Fran?ois,Janser, Philipp,Vulpetti, Anna,W?lchli, Rudolf,Beerli, Christian,Littlewood-Evans, Amanda,Dawson, Janet,Nuesslein-Hildesheim, Barbara,Wieczorek, Grazyna,Gutmann, Sascha,Scheufler, Clemens,Hinniger, Alexandra,Zimmerlin, Alfred,Funhoff, Enrico G.,Pulz, Robert,Cenni, Bruno
supporting information, p. 5102 - 5118 (2020/06/10)
Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.
Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4
Mori, Daisuke,Kimura, Hiroyuki,Kawashima, Hidekazu,Yagi, Yusuke,Arimitsu, Kenji,Ono, Masahiro,Saji, Hideo
, p. 4200 - 4210 (2019/08/12)
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with 99mTc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 99mTc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (?19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, 99mTc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 99mTc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.
COMBINATION OF CHIMERIC ANTIGEN RECEPTOR THERAPY AND AMINO PYRIMIDINE DERIVATIVES
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Page/Page column 267; 268; 275, (2017/04/29)
The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a BTK inhibitor, e.g., an amino pyrimidi
