Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands (original) (raw)
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Bioorganic & Medicinal Chemistry, 2009
Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile a b s t r a c t New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB 1 receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB 1 receptor, with K i concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB 1 selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB 1 binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB 1 selective compounds 4 and 52 act as antagonists/inverse agonists.
2008
The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB 1 and hCB 2 receptor affinity. Compounds bearing 2,4dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1 . On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB 2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB 1 receptor (K i (CB 2 )/K i (CB 1 ) ) 140.7). Derivative 30, the most potent hCB 1 ligand (K i ) 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC 50 ∼1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
European Journal of Medicinal Chemistry, 2011
New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB 1 K i ¼ 2.3 nM, CB 1 SI ¼ 163.6) showed CB 1 receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2 mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB 2 K i ¼ 0.51 nM, CB 2 SI ¼ 30.0) showed significant affinity and selectivity for the CB 2 receptor. The results presented here show that the 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide may serve as an effective scaffold for the design of either CB 1 or CB 2 receptor ligands.
Bioorganic & Medicinal Chemistry, 2003
Cannabinoids receptors, cellular elements of the endocannabinoid system, have been the focus of extensive studies because of their potential functional role in several important physiological and pathological processes. To further evaluate the properties of CB receptors, especially CB 1 and CB 2 subtypes, we have designed, using SR141716A as a benchmark, a new series of rigid 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides. Compounds 1 were synthesized from substituted 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and requisite amines. The various analogues were assayed for binding both to the brain and peripheral cannabinoid receptors (CB 1 and CB 2 ). Seven of the new compounds displayed very high in vitro CB 2 binding affinities, especially 1a, 1b, 1c, 1e, 1g, 1h and 1j which showed K i values of 0.34, 0.225, 0.27, 0.23, 0.385, 0.037 and 0.9 nM, respectively. Compounds 1a, 1b, 1c and 1h showed the highest selectivity for CB 2 receptor with K i (CB 1 ) to K i (CB 2 ) ratios of 6029, 5635, 5814 and 9810, respectively. Noticeably, 1h exhibited the highest affinity and selectivity for CB 2 receptors. #
European journal of medicinal chemistry, 2016
Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c] pyrazoles emerged as potent CB 2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c] pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB 1 and CB 2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB 2 receptor affinity (K i ¼ 4 nM) and remarkable selectivity (K i CB 1 /K i CB 2 ¼ 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: K i ¼ 6 nM), for the bornyl analogue (compound 14: K i ¼ 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: K i ¼ 69 nM). Compounds 10 and 14 were also highly selective for the CB 2 receptor (K i CB 1 /K i CB 2 > 1000), whereas compound 6 was relatively selective (K i CB 1 /K i CB 2 ¼ 27). The four compounds were also subjected to GTPgS binding analysis showing antagonist/inverse agonist properties (IC 50 for compound 14 ¼ 27 nM, for 15 ¼ 51 nM, for 10 ¼ 80 nM and for 6 ¼ 294 nM), and this activity was confirmed for the three more active compounds in a CB 2 receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted Abbreviations: D 9-THC, D 9-Tetrahydrocannabinol; 2-AG, 2-Arachidonoylglycerol; CB 1 , cannabinoid receptor type 1; CB 2 , cannabinoid receptor type 2; CNS, Central nervous system; TRPV1, transient receptor potential vanilloid-1 channel; PPAR, peroxisome proliferator-activated receptor; GTPgS, guanosine 5 0-O-[gamma-thio]triphosphate; LPS, lipopolysaccharide; DDQ, 2,3dichloro-5,6-dicyano-1,4-benzoquinone; hCB 2 , human CB 2 receptor; FC, flash chromatography.
Journal of Medicinal Chemistry, 2009
Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities. Thorough structure-activity relationship (SAR) studies to optimize the pyrazole substituents led to several novel CB1 antagonists with K i e 5 nM and with acceptable metabolic stability with human liver microsomes. Among these analogues, we identified 5-(4-cyclopropylphenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-pyrrolidin-1-yl-1H-pyrazole-3-carboxamide (11r), which exhibited a favorable pharmacological profile with outstanding efficacy in reducing serum lipid parameters of metabolic syndrome compared to clinical references.
Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction
Molecules, 2021
Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
European Journal of Medicinal Chemistry, 2015
During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB 2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (K i in the low nM range) and selectivity for the CB 2 receptor and both resulted to be antagonists/inverse agonists in [ 35 S]-GTPgS binding analysis and in an in vitro CB 2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB 2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB 2 receptor inactive state model.
Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands
Molecules, 2019
In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c–j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transi...
Monatshefte für Chemie - Chemical Monthly, 2007
The syntheses of several new 3-and 5-(4chloro-2-hydroxyphenyl)-5-and -3-(2,4-dichlorophenyl)-1alkylpyrazoles are reported. These syntheses started from simple chlorophenols, 2,4-dichlorobenzaldehyde or ethyl 2,4dichlorobenzoate in order to prepare pyrazoles bearing three and four chloro substituents in certain positions. The affinity of these compounds towards the CB 1 type cannabinoids receptors was then evaluated in human brain tissues (frontal cortex). The results showed that some of the compounds exhibit affinity towards this kind of receptors in the micromolar range.