CC-97489(CC-97489) - 药物靶点：FAAH x MAGL_专利_临床

概要

基本信息

药物类型

小分子化药

别名

FAAH/MGLL dual inhibitor

靶点

FAAH x MAGL

作用机制

FAAH抑制剂(脂肪酸酰胺水解酶抑制剂)、MAGL抑制剂(单甘油酯脂肪酶抑制剂)

治疗领域

神经系统疾病

在研适应症-

非在研适应症

神经系统疾病

原研机构

Bristol-Myers Squibb Pharmaceuticals Ltd.

在研机构

Celgene Corp.

非在研机构

Bristol Myers Squibb Co.

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

2

项与 CC-97489 相关的临床试验

NCT05065541 / Completed临床1期

A Phase 1, Open-label, Multi-part Positron Emission Tomography (PET) Imaging Study to Evaluate the Biodistribution and Radiation Dosimetry of the Monoacylglycerol Lipase (MGLL) PET Ligand [18F]T-401 and to Evaluate Fatty Acid Amide Hydrolase (FAAH) and MGLL Enzyme Availability in the Central Nervous System Using [11C]MK-3168 and [18F]T-401 PET Ligands Before and After Oral Administration of Single and Multiple Doses of CC-97489 in Healthy Adult Subjects

The purpose of this study is to evaluate enzyme availability in the central nervous system before and after CC-97489 administration in healthy participants

开始日期2021-09-24

申办/合作机构

Celgene Corp.

NCT05099822 / Terminated临床1期

A Phase 1, Randomized, Double-blind, Placebo-controlled, Single-center, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of CC-97489 in Healthy Adult Subjects

This study aims to evaluate the safety, tolerability, of CC-97489

开始日期2020-03-13

申办/合作机构

Celgene Corp.

100 项与 CC-97489 相关的临床结果

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100 项与 CC-97489 相关的转化医学

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100 项与 CC-97489 相关的专利（医药）

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27

项与 CC-97489 相关的文献（医药）

2023-06-30·International journal of molecular sciences

Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis.

Article

作者: Malinowska, Barbara ; Kozłowska, Hanna ; Toczek, Marek ; Remiszewski, Patryk ; Krzyżewska, Anna ; Schlicker, Eberhard ; Ryszkiewicz, Piotr

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.

2023-01-01·Physiological Reports

The endocannabinoid systemʼs involvement in motor development relies on cannabinoid receptors, TRP channels, and Sonic Hedgehog signaling

Article

作者: Ali, Declan W. ; Khara, Lakhan S.

AbstractThe endocannabinoid system (eCS) plays critical roles in locomotor function and motor development; however, the roles of non‐canonical cannabinoid receptor systems such as transient receptor potential (TRP) channels and the Sonic Hedgehog (SHH) signaling pathway in conjunction with the eCS in sensorimotor development remains enigmatic. To investigate the involvement of canonical and non‐canonical cannabinoid receptors, TRP channels, and the SHH pathway in the development of sensorimotor function in zebrafish, we treated developing animals with pharmacological inhibitors of the CB1R, CB2R, TRPA1/TRPV1/TRPM8, and a smoothened (SMO) agonist, along with inhibitors of the eCS catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) during the first ~24 h of zebrafish embryogenesis. Locomotor function was examined by assessing touch‐evoked escape swimming at 2 days post‐fertilization. We report that FAAH inhibition had no effect on swimming while MAGL inhibition using JZL 184 reduced swimming distance and the dual FAAH/MAGL inhibitor JZL 195 impaired swimming distance and mean swimming velocity. The CB1R antagonist AM 251 prevented locomotor deficits caused by eCS perturbation but the CB2R antagonist AM 630 did not. Inhibition of TRPA1/TRPV1/TRPM8 using AMG 9090 rescued the locomotor reductions caused by FAAH/MAGL inhibition, but not by MAGL inhibition alone. The SMO agonist purmorphamine attenuated the effects of JZL 184 and JZL 195 on swimming distance, but not mean velocity. Together, these findings provide one of the first investigations examining the interactions between the eCS and its non‐canonical receptor systems in vertebrate motor development.

2022-11-01·Archiv der Pharmazie

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors

Article

作者: Jaiswal, Shivani ; Gupta, Garima ; Ayyannan, Senthil R.

AbstractFatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2‐arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH–MAGL inhibition properties. Phenyl [4‐(piperidin‐1‐ylmethyl)phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC50 = 19 nM), benzyl (1H‐benzo[d]imidazol‐2‐yl)carbamate (3h) was the most potent FAAH inhibitor (IC50 = 55 nM), and phenyl (6‐fluorobenzo[d]thiazol‐2‐yl)carbamate (2i) egressed as a nonselective dual FAAH–MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent‐reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood–brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug‐likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.

100 项与 CC-97489 相关的药物交易

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