Bioisosteric replacement of dihydropyrazole of 4S-(−)-3-(4-chlorophenyl)-N-methyl-N′-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole

Srivastava, B.; Soni, Rina; Joharapurkar, Amit; Sairam, Kalapatapu V.V.M.; Patel, Jayendra Z.; Goswami, Amitgiri; Shedage, Sandeep A.; Kar, Sidhartha S; Salunke, Rahul P.; Gugale, Shivaji B.; Dhawas, Amol K.; Kadam, Pravin; Mishra, Bhupendra; Sadhwani, Nisha; Unadkat, Vishal; Mitra, Prasenjit; Jain, Mukul; Patel, Pankaj

doi:10.1016/j.bmcl.2007.12.036

Cited by 14 publications

(3 citation statements)

References 16 publications

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“…The CB 1 receptor binding data revealed that the thiazole derivative 47 has at least a 4-fold higher CB 1 affinity than its regioisomer 48, which contains a different pattern of chlorine substitution on both aromatic rings. The same phenomenon was observed in the oxazole series 45 and 46, indicating the importance of nitrogen position in the 5-membered ring [76,78,86].…”

Section: Oxazoles and Thiazolessupporting

confidence: 75%

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Lee¹,

Choi²,

Pak³

2009

CTMC

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Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB(1)R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB(1)R blockers for treatment of obesity ensued. However, abandoning this CB(1)R therapeutic target for anti-obesity drug development seems to be premature, since there are a number of potential approaches have been uncovered to circumvent the problems of the current agents. In this review, we summarize advances that have been made and the status of studies of a diverse array of CB(1)R antagonists that have been identified mainly based on modifications of the first-in-class CB(1)R antagonist, rimonabant. Various approaches have been employed to design these analogs, such as bioisosteric replacement, introduction of conformational constraints, scaffold hopping and ligand-based molecular modeling. In addition, current approaches that have been uncovered to avoid psychiatric side effects of CB(1)R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB(1)R antagonists, allosteric modulators of CB(1)R, and neutral antagonists for CB(1)R is also discussed in this review.

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Section: Oxazoles and Thiazolessupporting

confidence: 75%

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Lee¹,

Choi²,

Pak³

2009

CTMC

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“…Therefore, it appears that the amide group should be replaced by a moiety capable of acting as a hydrogen-bond acceptor so not to completely lose this binding interaction. A number of relevant derivatives with bioisosteric substitutes of the amide group by sulphonamide (Srivastava et al , 2008), oxadiazole (Lee et al , 2008) and imidazol-4-thione (Wu et al , 2009) have been attempted; however, these derivatives either lost binding affinity for CB 1 or retained inverse agonism. In terms of size and spatial requirements, a ketone is an excellent replacement for an amide, but any functional consequences of a small, partially negative charge residing on the oxygen of the ketone are difficult to foresee.…”

Section: Discussionmentioning

confidence: 99%

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

Goonawardena

Plano

Robinson

et al. 2015

Behavioural Pharmacology

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The brain endocannabinoid system is a potential target for the treatment of psychiatric and metabolic conditions. Here, a novel CB1 receptor antagonist (ABD459) was synthesized and assayed for pharmacological efficacy in vitro and for modulation of food consumption, vigilance staging and cortical electroencephalography in the mouse. ABD459 completely displaced the CB1 agonist CP99540 at a Ki of 8.6 nmol/l, and did not affect basal, but antagonized CP55940-induced GTPγS binding with a KB of 7.7 nmol/l. Acute ABD459 (3–20 mg/kg) reliably inhibited food consumption in nonfasted mice, without affecting motor activity. Active food seeking was reduced for 5–6 h postdrug, with no rebound after washout. Epidural recording of electroencephalogram confirmed that ABD459 (3 mg/kg) robustly reduced rapid eye movement (REM) sleep, with no alterations of wakefulness or non-REM sleep. Effects were strongest during 3 h postdrug, followed by a progressive washout period. The CB1 antagonist AM251 (3mg/kg) and agonist WIN-55,212-2 (WIN-2: 3 mg/kg) also reduced REM, but variously affected other vigilance stages. WIN-2 caused a global suppression of normalized spectral power. AM251 and ABD459 lowered delta power and increased power in the theta band in the hippocampus, but not the prefrontal cortex. The neutral antagonist ABD459 thus showed a specific role of endocannabinoid release in attention and arousal, possibly through modulation of cholinergic activity.

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“…Ibipinabant (SLV‐319), 4S‐(–)‐3‐(4‐Chlorophenyl)‐N‐methyl‐N'‐[(4‐chlorophenyl)‐sulfonyl]‐4‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamidine, was synthesized at Zydus based on structural similarity to rimonabant. The design was based on the bioisosteric replacement of rimonabant's pyrazole moiety with dihydropyrazole(49). N‐aminomorpholine was the optimal side chain and the bisulfate salt was best for bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Ward

Raffa

2011

Obesity

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Bioisosteric replacement of dihydropyrazole of 4S-(−)-3-(4-chlorophenyl)-N-methyl-N′-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole

Cited by 14 publications

References 16 publications

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

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