Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template

Three new positron emission tomography (PET) radiotracers of interest to our functional neuroimaging and translational oncology programs have been prepared through new developments in [11C]CO2 fixation chemistry. [11C]QZ (glutaminyl cyclase) was prepared via a tandem trapping of [11C]CO2/intramolecular cyclization; [11C]tideglusib (glycogen synthase kinase-3) was synthesized through a tandem trapping of [11C]CO2 followed by an intermolecular cycloaddition between a [11C]isocyanate and an isothiocyanate to form the 1,2,4-thiadiazolidine-3,5-dione core; [11C]ibrutinib (Bruton’s tyrosine kinase) was synthesized through a HATU peptide coupling of an amino precursor with [11C]acrylic acid (generated from [11C]CO2 fixation with vinylmagnesium bromide). All radiochemical syntheses are fully-automated on commercial radiochemical synthesis modules and provide radiotracers in 1 – 5% radiochemical yield (non-corrected, based upon [11C]CO2). All three radiotracers have advanced to rodent imaging studies and preliminary PET imaging results are also reported.

show abstract

“…QZ is a closely related desmethyl analog of a recently reported QC inhibitor (IC 50 = 123 nM), Figure 2. 23 …”

Section: Resultsmentioning

confidence: 99%

Synthesis of Diverse ¹¹C-Labeled PET Radiotracers via Direct Incorporation of [¹¹C]CO₂

et al. 2016

View full text Add to dashboard Cite

show abstract

“…They all contain zinc-binding group, a hydrogen-bonding donor and an aromatic group to interact with Phe325 in the pocket as a critical amino acid for potent binding. [18][19][20][21][22] Recently, a new binding pocket was reported with an orientation opposite to that of the Phe325 pocket, based on the discovery of SEN177. Crystal studies of the SEN177-hQC complex showed two interactions between the enzyme and the inhibitor in terms of inhibitor orientation: the pyridine ring with Trp207 and the uorine atom of 2-uoropyridine with the hydrogen atom of His330 (ref.…”

Section: Introductionmentioning

confidence: 99%

“…24 In the present work, both computational and experimental studies were performed to design two new potential inhibitory hQC series based on structural knowledge of the hQC substrates and known hQC inhibitors. [19][20][21][22]25 To the best of our knowledge, most potential hQC inhibitors contain substituted urea or thiourea scaffolds. The potency of thiourea derivatives are greater than that of corresponding ureas.…”

Section: Introductionmentioning

confidence: 99%

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…To inhibit the activity of QC, a few small molecule QC inhibitors have been reported [12][13][14][15][16]. These chemicals contain an aromatic motif tethered to an imidazole moiety, where the aromatic ring matches the hydrophobic space at the entrance of the active site and the imidazole moiety binds the catalytic zinc ion at the bottom of the pocket.…”

mentioning

confidence: 99%

Can Small Molecule Inhibitors of Glutaminyl Cyclase Be Used as a Therapeutic for Alzheimer'S Disease?

2017

Future Med. Chem.

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a multifactorial and socioeconomically burdensome disease. In view of the failures of anti-AD candidates, we should try to rethink what we did before and what we should do next, in part at least. Research shows that the more neurotoxic factor, pyroglutamate-Aβs, and the more important inflammatory mediators, pyroglutamate-CCL2, both contribute to the initiation of AD specifically and the generation of N-terminal intramolecular cyclization catalyzed by glutaminyl cyclase quality control, the over-expression of which correlates positively with the severity of AD. Subsequently, lowering pyroglutamate-Aβs and pyroglutamate-CCL2 levels by quality control inhibition using small molecule inhibitors could be expected as an amazing strategy for the prevention and treatment of AD. Alzheimer's disease (AD) is a systematically chronic neurodegenerative disease characterized by diminution of cognitive function, memory, neurobehavioral manifestations, social withdrawal and other behavioral symptoms. AD is the most common cause of dementia in aging and accounts for 60-80% of all cases. The prevalence of AD has increased dramatically over the past decade and is expected to become even worse in the future owing to increased life expectancy. Unfortunately, we have almost no idea about the exact pathology of this multifactorial disease, and there is no cure, at least no disease modifying agents, for this socioeconomically burdensome disease. For these reasons, demand for development of appropriate prevention and/or treatment options for AD will continue to grow rapidly.As one of the hallmarks, extracellular amyloid plaques contribute to the death of neurons and development of AD. β-Amyloid (Aβ) pathology is well documented, and the Aβ cascade hypothesis has been one of the main hypotheses. However, the fact is no candidate targeting Aβ pathology directly has passed through clinical trials including the failure of Lilly's solanezumab and Merck's verubecestat. Obviously, the development of anti-AD agents is a world challenge now. We cannot judge that the amyloid cascade hypothesis is flawed even now, but is Aβ aggregate the reasonable target for the discovery of anti-AD agents? Do we have any 'misunderstanding' about the AD pathology? What is the problem with the development strategy we use? Maybe it is the time for us to change our chair and rethink in part at least what we saw, what we did, what we learned and what we should do next.Many studies confirm that the formation of Aβ plaques, mainly composed of Aβ 42 and Aβ 40 , has no direct effects on the development of neurodegeneration and other clinical AD symptoms. These plaques can be detected in both AD brains and normal brains. What is the pathological difference between these two types of brain? In recent years, a variety of N-truncated Aβs have been identified only in AD brains including pyroglutamate-Aβs (pE-Aβs), which are the generations of Aβs undergoing N-terminal truncation by two or ten amino acids and following cyclization of resulting N-te...

show abstract

Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template

Cited by 32 publications

References 19 publications

Synthesis of Diverse ¹¹C-Labeled PET Radiotracers via Direct Incorporation of [¹¹C]CO₂

Synthesis of Diverse ¹¹C-Labeled PET Radiotracers via Direct Incorporation of [¹¹C]CO₂

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

Can Small Molecule Inhibitors of Glutaminyl Cyclase Be Used as a Therapeutic for Alzheimer'S Disease?

Contact Info

Product

Resources

About

Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template

Cited by 32 publications

References 19 publications

Synthesis of Diverse 11C-Labeled PET Radiotracers via Direct Incorporation of [11C]CO2

Synthesis of Diverse 11C-Labeled PET Radiotracers via Direct Incorporation of [11C]CO2

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

Can Small Molecule Inhibitors of Glutaminyl Cyclase Be Used as a Therapeutic for Alzheimer'S Disease?

Contact Info

Product

Resources

About

Synthesis of Diverse ¹¹C-Labeled PET Radiotracers via Direct Incorporation of [¹¹C]CO₂

Synthesis of Diverse ¹¹C-Labeled PET Radiotracers via Direct Incorporation of [¹¹C]CO₂