1031367-64-2

Upstream product

• 1031367-55-1 C₂₄H₂₃NO₄ 
• 58574-03-1 4'-Hydroxybiphenyl-4-carboxylic acid 
• 499239-74-6 C₁₃H₉ClO₂ 
• 40501-41-5 methyl 4'-hydroxy-4-biphenylcarboxylate 
• 2328-12-3 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline monohydrochloride 

Relevant academic research and scientific papers

New tetrahydroisoquinoline derivatives overcome pgp activity in brain-blood barrier and glioblastoma multiforme in vitro

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhib

A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression

P-glycoprotein (P-gp) is a membrane protein responsible for the active transport of several endogenous and exogenous substances. It constitutes a defense mechanism and, at the same time, it severely compromises the success rate of antitumor chemotherapy. In this study a small library of alkyl/oxyalkyl derivatives of MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], a well-known P-gp inhibitor, was synthesized through straightforward functionalization of the phenolic group present in the structure of MC70. All compounds were characterized for their effect on P-gp, proving capable of blocking P-gp-mediated calcein-AM efflux with micromolar potency, following their ability to act as high-affinity substrates of this transporter. Excitingly, compound 4 [6,7-dimethoxy-2-((4′-butoxybiphen-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline] exhibited low nanomolar potency (5.2 nm) and had a peculiar activity profile, acting both as a positive allosteric modulator and as a substrate of the transporter. A new and more efficient synthesis of MC70 is also described. Simple chemical modification of MC70, a well-known but rather nonselective P-glycoprotein (P-gp) inhibitor, led to a very potent and selective P-gp ligand (EC50=5.2 nm). The derivative displayed an intriguing double-faced mechanism of action, acting as both substrate and modulator. The synthesis of MC70 was also greatly improved, using a straightforward and protecting-group-free Suzuki-Miyaura coupling of halophenol.

Comparison of in vitro assays in selecting radiotracers for in vivo P-glycoprotein PET imaging

Positron emission tomography (PET) imaging of P-glycoprotein (P-gp) in the blood-brain barrier can be important in neurological diseases where P-gp is affected, such as Alzheimer’s disease. Radiotracers used in the imaging studies are present at very smal

Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood-Brain Barrier

P-Glycoprotein (P-gp), along with other transporter proteins at the blood-brain barrier (BBB), limits the entry of many pharmaceuticals into the brain. Altered P-gp function has been found in several neurological diseases. To study the P-gp function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half-life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(4-fluorophenyl)oxazole (1a), 2-biphenyl-4-yl-2-fluoroethoxy-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2), and 5-(1-(2-fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen (3). Compounds were characterized as P-gp substrates in vitro, and Mdr1a/b(-/-)Bcrp1(-/-) and wild-type mice were used to assess the substrate potential in vivo. Comparison was made to (R)-[11C]verapamil, which is currently the most frequently used P-gp substrate. Compound [18F]3 was performing the best out of the new radiopharmaceuticals; it had 2-fold higher brain uptake in the Mdr1a/b(-/-)Bcrp1(-/-) mice compared to wild-type and was metabolically quite stable. In the plasma, 69% of the parent compound was intact after 45 min and 96% in the brain. Selectivity of [18F]3 to P-gp was tested by comparing the uptake in Mdr1a/b(-/-) mice to uptake in Mdr1a/b(-/-)Bcrp1(-/-) mice, which was statistically not significantly different. Hence, [18F]3 was found to be selective for P-gp and is a promising new radiopharmaceutical for P-gp PET imaging at the BBB. (Chemical Equation).

6,7-DIOXYALKYLTETRAHYDROISOQUINOLINE COMPOUNDS

The present invention relates to a 6,7-dioxyalkyltetrahydroisoquinoline compound, or a salt or solvate thereof according to formula I: (formula I), (I) wherein R represents hydrogen or a fluorinated alkyl group, and R2 and R3 independently represents hydrogen or an alkyl group.

4-Biphenyl and 2-naphthyl substituted 6,7-dimethoxytetrahydroisoquinoline derivatives as potent P-gp modulators

Starting from lead compound 1 (EC50 = 1.64 μM), its non-basic nucleus has been conformationally restricted by 4-biphenyl and 2-naphthyl moieties. In each series we investigated if the presence of H-bond donor or acceptor substituents, the basic