Anti-inflammatory effect of LA 2851 and reference drugs on some models of inflammation. Investigation of the mechanism of action

Junien, Jean‐Louis; Lakatos, C; Brohon, J.; Guillaume, M.; Sterne, J

doi:10.1007/bf01965927

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…To test this possibility, we injected WT mice with metformin, which has a short half-life (2.7 h) in mice (24), at 8 a.m. and measured mRNA levels of core clock genes mPer1, mPer2, Clock, and Bmal1 at 8 a.m. (no injection), 1 p.m., 6 p.m., 10 p.m., 2 a.m., and 7 a.m. in the heart, skeletal muscle, and fat. Consistent with our earlier results, metformin injection induced AMPK activity and led to mPer2 degradation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2

Yang

Yamazaki

et al. 2007

Journal of Biological Chemistry

214

131

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Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase I⑀ (CKI⑀), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKI⑀, resulting in increased CKI⑀ activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK ␣2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.Animal behavior, including spontaneous locomotion, sleeping, eating, and drinking, follows a 24-h light-dark (LD) 2 cycle of the environment. The master pacemaker for the rhythmic behavior lies in the suprachiasmatic nucleus (SCN) of the hypothalamus (1). The SCN neurons, cued by the LD cycle, orchestrate the circadian rhythms of peripheral clocks that reside in most cells of the body. The pacemaker, both in the SCN and in peripheral tissues, consists of a self-sustaining near 24-h rhythm in the expression of core clock genes. A central component of this pacemaker is the negative-feedback loop, which results from Per and Cry proteins suppressing their own transcription with a precisely timed lag. A key regulator of the period length is casein kinase I⑀ (CKI⑀) (2). CKI⑀ and its homolog CKI␦ regulate the circadian period by phosphorylating mammalian Per proteins (3-6). The role of CKI⑀ in mammalian circadian rhythm is best illustrated by the semidominant mutation in hamster CKI⑀, tau (7). CKI⑀ tau is a highly specific gain-of-function mutation that increases the CKI⑀ kinase activity on Per proteins. CKI⑀-mediated phosphorylation induces proteasome-mediated degradation of Per proteins, leading to circadian phase advance and shortened period length (8).AMPK, by sensing the rise in AMP level under energy-deprived conditions (9), maintains energy homeostasis by stimulating ATP production and suppressing ATP-consuming processes such as synthesis of macromolecules (10). The catalytic subunit of AMPK has two isoforms, ␣1 (11) and ␣2 (12). Mice with a knockout (KO) of either AMPK ␣1 or AMPK ␣2 are viable (13,14), but mice with a KO of both ␣1 and ␣2 are not viable, 3 indicating that the two isoforms have partially redundant functions. In the hypothalamus, AMPK maintains energy homeostasis at...

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Section: Resultsmentioning

confidence: 99%

Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2

Yang

Yamazaki

et al. 2007

Journal of Biological Chemistry

214

131

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“…The rat RPA reaction has often been used as an in vivo model to test the efficacy of anti-inflammatory drugs (25)(26)(27)(28)(29)(30)(31)). Yet, despite FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

The Arthus Reaction in Rodents: Species-Specific Requirement of Complement

Szalai

Digerness²,

Agrawal

et al. 2000

The Journal of Immunology

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We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

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“…The synthesis of these compounds was carried out according to Scheme 37. [1,3,5]triazine (LA 2851, Dametralast, 39b) showed combination of two principal effects that are useful in asthma therapy, namely bronchodilator 145,146 and antiallergic [145][146][147] activities, as well as low toxicity. Anti-inflammatory properties (not attributed to cyclooxygenase inhibition or mediator release) were also identified for LA 2851.…”

Section: Scheme 85mentioning

confidence: 99%

“…Anti-inflammatory properties (not attributed to cyclooxygenase inhibition or mediator release) were also identified for LA 2851. 148 It was found that LA 2851 inhibited to some extent PDE, but this enzyme was not its primary target. The investigations on the mechanism of action of LA 2851…”

Section: Scheme 85mentioning

confidence: 99%

Pyrazolo[1,5-a][1,3,5]triazines (5-Aza-9-deazapurines): Synthesis and Biological Activity

Dolzhenko¹,

Dolzhenko²,

Chui³

2008

HETEROCYCLES

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The present review gives an account on the synthetic routes to pyrazolo [1,5-a] [1,3,5]triazine system, which is an isostere of purine, and polyfused systems bearing this heterocyclic core. Data concerning biological activity of compounds with pyrazolo[1,5-a] [1,3,5]triazine skeleton are also discussed. CONTENTS 1. INTRODUCTION 2. SYNTHESIS BY ANNELATION OF THE 1,3,5-TRIAZINE RING ONTO A PYRAZOLE SCAFFOLD 2.1. Four-bond formation (3+1+1+1) through cyclization of 3(5)-aminopyrazoles with two carbon and one nitrogen atoms.2.2. Three-bond formation (3+2+1) through cyclization of 3(5)-aminopyrazoles with reagents introducing C-N fragment and one carbon atom.2.3. Two-bond formation (3+3) through cyclization of 3(5)-aminopyrazoles with reagents introducing C-N-C fragment. Two-bond formation (3+3) through cyclization of 1-acylpyrazolidinediones with reagentsintroducing N-C-N fragment. Two-bond formation (4+2) through cyclization of 5-aminopyrazoles having carbon atom at N1with reagents introducing C-N fragment.2.6. Two-bond formation (4+2) through cyclization of pyrazoles having N-C appendage at C3(5) with reagents introducing C-N fragment.2.7. Two-bond formation (5+1) through cyclization of 5-aminopyrazoles having C-N appendage at N1 with one carbon atom. HETEROCYCLES, Vol. 75, No. 7, 2008 15752.8. Two-bond formation (5+1) through cyclization of pyrazoles having N-C-N appendage at C3 (5) with one carbon atom.2.9. One bond formation through intramolecular cyclization of 5-aminopyrazoles having C-N-C appendage at N1.2.10. One bond formation through intramolecular cyclization of pyrazoles having N-C-N-C appendage at C3(5). SYNTHESIS BY ANNELATION OF THE PYRAZOLE RING ONTOA 1,3,5-TRIAZINE SCAFFOLD 4. SYNTHESIS BY CONCURRENT FORMATION OF BOTH THE 1,3,5-TRIAZINE AND PYRAZOLE RINGS 5. SYNTHESIS VIA RING TRANSFORMATION REACTIONS 6. BIOLOGICAL ACTIVITY OF PYRAZOLO[1,5-a][1,3,5]TRIAZINE DERIVATIVES 6.1. Enzyme inhibitors 6.2. Receptor ligands 6.3. Miscellaneous biological activities 7. CONCLUSION 1576 HETEROCYCLES, Vol. 75, No. 7, 2008 syntheses and pharmacological data on the more interesting examples of bioactive compounds are discussed separately in the Section 6 of this review. Within the review we collectively categorized the common approaches to the synthesis of pyrazolo[1,5-a][1,3,5]triazines into: (A) annelation of the 1,3,5-triazine ring onto a pyrazole scaffold; (B) annelation of the pyrazole ring onto a 1,3,5-triazine scaffold; (C) concurrent formation of both the 1,3,5-triazine and pyrazole ring; (D) syntheses via ring transformation reactions. SYNTHESIS BY ANNELATION OF THE 1,3,5-TRIAZINE RING ONTO A PYRAZOLE SCAFFOLDThe 1,3,5-triazine ring annelation strategy is a very versatile synthetic approach for the preparation of pyrazolo[1,5-a][1,3,5]triazines. This strategy represents the most frequently utilized route to the formation of the pyrazolo[1,5-a][1,3,5]triazine ring system. Suitably functionalized pyrazoles can be cyclized to pyrazolo[1,5-a][1,3,5]triazines according to the following schematically represented p...

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Anti-inflammatory effect of LA 2851 and reference drugs on some models of inflammation. Investigation of the mechanism of action

Cited by 8 publications

References 23 publications

Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2

Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2

The Arthus Reaction in Rodents: Species-Specific Requirement of Complement

Pyrazolo[1,5-a][1,3,5]triazines (5-Aza-9-deazapurines): Synthesis and Biological Activity

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