Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of ...traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.
Muscarinic acetylcholine receptors (mAChR), including M4, draw attention as therapeutic targets for several neurodegenerative diseases including Alzheimer's disease (AD). PET imaging of M4 positive ...allosteric modulator (PAM) allows qualification of the distribution as well as the expression of this receptor under physiological conditions and thereby helps to assess the receptor occupancy (RO) of a drug candidate. In this study, our aims were (a) to synthesize a novel M4 PAM PET radioligand 11CPF06885190 (b) to evaluate the brain distribution of
CPF06885190 in nonhuman primates (NHP) and (c) to analyze its radiometabolites in the blood plasma of NHP. Radiolabeling of
CPF06885190 was accomplished via N-methylation of the precursor. Six PET measurements were performed using two male cynomolgus monkeys, where three PET measurements were at baseline, two after pretreatment with a selective M4 PAM compound CVL-231 and one after pretreatment with donepezil. The total volume of distribution (
) of
CPF06885190 was examined using Logan graphical analysis with arterial input function. Radiometabolites were analyzed in monkey blood plasma using gradient HPLC system. Radiolabeling of
CPF06885190 was successfully accomplished and the radioligand was found to be stable in the formulation, with radiochemical purity exceeding 99% 1 h after the end of the synthesis.
CPF06885190 was characterized in the cynomolgus monkey brain where a moderate brain uptake was found at the baseline condition. However, it showed fast wash-out as it dropped to half of the peak at around 10 min. Change of
from baseline was around -10% after pretreatment with a M4 PAM, CVL-231. Radiometabolite studies showed relatively fast metabolism. Although sufficient brain uptake of
CPF06885190 was observed, these data suggest that
CPF06885190 might have too low specific binding in the NHP brain to be further applied in PET imaging.
As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography ...(PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (B max) and biodistribution determination, a PET-specific structure–activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS “cold tracer” method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the “cold tracer” study. In subsequent non-human primate (NHP) PET imaging studies, 18F8 showed rapid brain uptake and high target specificity, indicating that 18F8 is a promising PDE4B-preferring radioligand for clinical PET imaging.
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the ...principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.
Herein, we report a general and simplified synthesis of fluorophosphonates directly from p‐nitrophenylphosphonates. This FP on‐demand reaction is mediated by a commercially available ...polymer‐supported fluoride reagent that produces a variety (25 examples) of fluorophosphonates in high yields while only requiring reagent filtration for pure fluorophosphonate isolation. This reaction protocol facilitates the rapid profiling of serine hydrolases with diverse and novel sets of activated phosphonates with differential proteome reactivity. Moreover, slight modification of the procedure into a reaction‐to‐assay format has enabled additional screening efficiency.
Not too demanding: A robust and purification‐free, one‐step synthesis has been developed to enable the on‐demand preparation of structurally diverse fluorophosphonates from a stable, and storable “toolbox” of readily accessible p‐nitrophenylphosphonates. Additionally, a reaction‐to‐assay protocol is highlighted that further facilitates the rapid screening of these valuable activity‐based probes.
Despite the important role of apolipoprotein E (apoE) secretion from astrocytes in brain lipid metabolism and the strong association of apoE4, one of the human apoE isoforms, with sporadic and late ...onset forms of Alzheimer's disease (AD) little is known about the regulation of astrocytic apoE. Utilizing annotated chemical libraries and a phenotypic screening strategy that measured apoE secretion from a human astrocytoma cell line, inhibition of pan class I histone deacetylases (HDACs) was identified as a mechanism to increase apoE secretion. Knocking down select HDAC family members alone or in combination revealed that inhibition of the class I HDAC family was responsible for enhancing apoE secretion. Knocking down LXRα and LXRβ genes revealed that the increase in astrocytic apoE in response to HDAC inhibition occurred via an LXR-independent pathway. Collectively, these data suggest that pan class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1.The first generation 5HT-4 partial agonist, 4-{4-4-Tetrahydrofuran-3-yloxy)-benzodisoxazol-3-yloxymethyl-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to ...N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma.
2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes.
3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation.
4.The effort concluded with identification of azetidines as second-generation 5HT
4
partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing ...unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres’ electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor–agonist interaction mode.
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening ...decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
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