AM 6545 - CAS 1245626-05-4
Category: Inhibitor
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Molecular Formula:
C26H23Cl2N5O3S
Molecular Weight:
556.46
COA:
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Targets:
Cannabinoid Receptor
Description:
AM 6545 has been found to be a CB1 antagonist and could probably be used as an appetite suppressant.
Purity:
≥98% by HPLC
Appearance:
White Solid
Synonyms:
5-[4-(4-Cyano-1-butyn-1-yl)phenyl]-1-(2,4-dichlorophenyl)-N-(1,1-dioxido-4-thiomorpholinyl)-4-methyl-1H-pyrazole-3-carboxamide
MSDS:
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InChIKey:
XBHQLFVDGLPBCK-UHFFFAOYSA-N
InChI:
InChI=1S/C26H23Cl2N5O3S/c1-18-24(26(34)31-32-13-15-37(35,36)16-14-32)30-33(23-11-10-21(27)17-22(23)28)25(18)20-8-6-19(7-9-20)5-3-2-4-12-29/h6-11,17H,2,4,13-16H2,1H3,(H,31,34)
Canonical SMILES:
CC1=C(N(N=C1C(=O)NN2CCS(=O)(=O)CC2)C3=C(C=C(C=C3)Cl)Cl)C4=CC=C(C=C4)C#CCCC#N
1.Peripherally restricted CB1 receptor blockers.
Chorvat RJ Bioorg Med Chem Lett. 2013 Sep 1;23(17):4751-60. doi: 10.1016/j.bmcl.2013.06.066. Epub 2013 Jul 4.
Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).
2.A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome.
Bowles NP;Karatsoreos IN;Li X;Vemuri VK;Wood JA;Li Z;Tamashiro KL;Schwartz GJ;Makriyannis AM;Kunos G;Hillard CJ;McEwen BS;Hill MN Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):285-90. doi: 10.1073/pnas.1421420112. Epub 2014 Dec 22.
Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus.
3.Protective role of cannabinoid CB1 receptors and vascular effects of chronic administration of FAAH inhibitor URB597 in DOCA-salt hypertensive rats.
Baranowska-Kuczko M;Kozłowska H;Kloza M;Karpińska O;Toczek M;Harasim E;Kasacka I;Malinowska B Life Sci. 2016 Apr 15;151:288-299. doi: 10.1016/j.lfs.2016.03.014. Epub 2016 Mar 9.
AIMS: ;This study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes.;MAIN METHODS: ;Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively.;KEY FINDINGS: ;In the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction.
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CAS 1245626-05-4 AM 6545

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