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Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consist of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea and α-substituted amide derivatives was developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogs, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation in the active site, as is critical for its potent activity.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Human glutaminyl cyclase (hQC) is an important enzyme for post-translational modification by converting the N-terminal glutaminyl and glutamyl into its pyroglutamate (pGlu) through cyclization. The tw...
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Up-regulated glutaminyl cyclase (QC) plays crucial roles in the initiation of Alzheimer's disease (AD) and kinds of chronic diseases mediated by inflammation. QC is supposed as a novel target for the ...
This is a seamless phase 2A-B multi-center, randomized, double blind, placebo-controlled, parallel group study of PQ912, an inhibitor of the glutaminyl cyclase enzyme. Phase 2A includes ad...
The purpose of this prospective clinical trial is to document the performance and clinical outcomes of Biomet Discovery Elbow.
To evaluate the effect of itraconazole (a potent cytochrome P450 isoenzyme [CYP]3A inhibitor) on the pharmacokinetics (PK) of olinciguat
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Circulating 38-kDa proteins that are internal peptide fragments of PLASMINOGEN. The name derives from the fact that they are potent ANGIOGENESIS INHIBITORS. Angiostatins contain four KRINGLE DOMAINS which are associated with their potent angiostatic activity.
Compounds that bind to and inhibit the action of ADENYLYL CYCLASES.
A non-hydrolyzable analog of GTP, in which the oxygen atom bridging the beta to the gamma phosphate is replaced by a nitrogen atom. It binds tightly to G-protein in the presence of Mg2+. The nucleotide is a potent stimulator of adenylate cyclase.
Compunds that bind to and activate GUANYLYL CYCLASE-C RECEPTORS.
One of the virulence factors produced by virulent BORDETELLA organisms. It is a bifunctional protein with both ADENYLATE CYCLASE and hemolysin components.
Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase 'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...