Ibipinabant

Last updated
Ibipinabant
Ibipinabant.svg
Clinical data
ATC code
  • none
Identifiers
  • 4S-(−)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.158.931 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H22Cl2N4O2S
Molar mass 501.43 g·mol−1
3D model (JSmol)
  • c2cc(Cl)ccc2C1=NN(C(NC)=NCS(=O)(=O)c3ccc(Cl)cc3)CC1c4ccccc4
  • InChI=1S/C24H22Cl2N4O2S/c1-27-24(28-16-33(31,32)21-13-11-20(26)12-14-21)30-15-22(17-5-3-2-4-6-17)23(29-30)18-7-9-19(25)10-8-18/h2-14,22H,15-16H2,1H3,(H,27,28)/t22-/m1/s1 X mark.svgN
  • Key:BSFKAVCGRDMWTK-JOCHJYFZSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1 antagonist. [1] It has potent anorectic effects in animals, [2] and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists. [3] [4] [5] SLV330, which is a structural analogue of Ibipinabant, was reported active in animal models related to the regulation of memory, cognition, as well as in addictive behavior. [6] [7] An atom-efficient synthesis of ibipinabant has been reported. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Taranabant</span> Chemical compound

Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 (CB1) inverse agonist that was investigated as a potential treatment for obesity due to its anorectic effects. It was discovered by Merck & Co.

<span class="mw-page-title-main">NESS-0327</span> Chemical compound

NESS-0327 is a drug used in scientific research which acts as an extremely potent and selective antagonist of the cannabinoid receptor CB1. It is much more potent an antagonist, and more selective for the CB1 receptor over CB2, than the more commonly used ligand rimonabant, with a Ki at CB1 of 350fM (i.e. 0.00035nM) and a selectivity of over 60,000x for CB1 over CB2. Independently, two other groups have described only modest nanomolar CB1 affinity for this compound (125nM and 18.4nM). Also unlike rimonabant, NESS-0327 does not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the CB1 receptor but does not produce any physiological effect of its own.

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.

<span class="mw-page-title-main">AM-630</span> Chemical compound

AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain. AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of many related derivatives.

<span class="mw-page-title-main">Org 28312</span> Chemical compound

Org 28312 is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water-soluble cannabinoid agonist suitable for intravenous use as an analgesic, but did not proceed to human trials, with the related compound Org 28611 chosen instead due to its better penetration into the brain. The structure-activity relationships of these compounds have subsequently been investigated further leading to the development of a number of more potent analogues, derived by cyclisation around the indole or piperazine rings.

<span class="mw-page-title-main">JWH-302</span> Chemical compound

JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with moderate affinity at both the CB1 and CB2 receptors. It is a positional isomer of the more common drug JWH-250, though it is slightly less potent with a Ki of 17 nM at CB1, compared to 11 nM for JWH-250. Because of their identical molecular weight and similar fragmentation patterns, JWH-302 and JWH-250 can be very difficult to distinguish by GC-MS testing.

<span class="mw-page-title-main">MN-25</span> Chemical compound

MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Ki of 8 nM at CB1 and 29 nM at CB2, which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).

<span class="mw-page-title-main">O-1269</span> Chemical compound

O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homolog O-1270 and the N-propyl homolog O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homolog O-1269. Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.

<span class="mw-page-title-main">CBS-0550</span> Chemical compound

CBS-0550 is a drug developed by Taisho Pharmaceutical, which acts as a potent and selective cannabinoid CB2 receptor agonist, with 1400x selectivity for CB2 over the related CB1 receptor. Unlike most cannabinoid agonists, CBS-0550 has good solubility in water, and in animal studies it was found to produce analgesic and anti-hyperalgesic effects. A number of related compounds have been developed with similar properties.

<span class="mw-page-title-main">LASSBio-881</span> Chemical compound

LASSBio-881 is a drug which acts as both a non-selective partial agonist of the CB1 and CB2 cannabinoid receptors, and also as an antagonist of the TRPV1 receptor, as well as having antioxidant effects. It has potent anti-inflammatory and anti-hyperalgesic effects in animal studies.

<span class="mw-page-title-main">LBP-1 (drug)</span> Chemical compound

LBP-1 is a drug originally developed by Organon for the treatment of neuropathic pain, It acts as a potent and selective cannabinoid receptor agonist, with high potency at both the CB1 and CB2 receptors, but low penetration of the blood–brain barrier. This makes LBP-1 peripherally selective, and while it was effective in animal models of neuropathic pain and allodynia, it did not produce cannabinoid-appropriate responding suggestive of central effects, at any dose tested.

<span class="mw-page-title-main">KM-233</span> Chemical compound

KM-233 is a synthetic cannabinoid drug which is a structural analog of Δ8-tetrahydrocannabinol (THC), the less active but more stable isomer of the active component of Cannabis. KM-233 differs from Δ8-THC by the pentyl side chain being replaced by a 1,1-dimethylbenzyl group. It has high binding affinity in vitro for both the CB1 and CB2 receptors, with a CB2 affinity of 0.91 nM and 13-fold selectivity over the CB1 receptor. In animal studies, it has been found to be a potential treatment for glioma, a form of brain tumor. Many related analogues are known where the 1,1-dimethylbenzyl group is substituted or replaced by other groups, with a fairly well established structure-activity relationship.

<span class="mw-page-title-main">S-444,823</span> Chemical compound

S-444,823 is a drug developed by Shionogi which is a cannabinoid agonist. It was developed as an antipruritic, and has moderate selectivity for the CB2 subtype, having a CB2 affinity of 18nM, and 32x selectivity over the CB1 receptor. In animal studies it showed analgesic effects and strongly reduced itching responses, but without producing side effects such as sedation and catalepsy that are seen with centrally acting CB1 agonists.

<span class="mw-page-title-main">JD5037</span> Chemical compound

JD5037 is an antiobesity drug candidate which acts as a peripherally-restricted cannabinoid inverse agonist at CB1 receptors. It is very selective for the CB1 subtype, with a Ki of 0.35nM, >700-fold higher affinity than it has for CB2 receptors.

<span class="mw-page-title-main">QMPSB</span> Chemical compound

QMPSB is an arylsulfonamide-based synthetic cannabinoid that has been sold as a designer drug.

<span class="mw-page-title-main">MCHB-1</span> Chemical compound

MCHB-1 is a benzimidazole derived drug which was researched as an analgesic but never developed for medical use. It acts as a potent agonist of the CB2 receptor, with an EC50 of 0.52nM at CB2, and ~30x selectivity over CB1 (Ki of 110nM at CB1 vs 3.7nM at CB2). It has been sold online as a designer drug, first being identified in Germany in December 2013.

<span class="mw-page-title-main">RQ-00202730</span> Chemical structure

RQ-00202730 is a benzimidazole derived drug that acts as a potent and highly selective agonist for the CB2 cannabinoid receptor, with a Ki value of 19nM at CB2 and more than 4000x selectivity over CB1, though it also shows some activity as an antagonist of the unrelated 5-HT2B serotonin receptor. It has analgesic and antiinflammatory effects in animal studies, and was developed for the treatment of irritable bowel syndrome, but was ultimately discontinued from development following disappointing results in Phase II clinical trials.

<span class="mw-page-title-main">JWH-369</span> Chemical compound

JWH-369 ((5-(2-chlorophenyl)-1-pentyl-1H-pyrrol-3-yl)(naphthalen-1-yl)methanone) is a synthetic cannabinoid from the naphthoylpyrrole family which acts as a potent agonist of the CB1 (Ki = 7.9 ± 0.4nM) and CB2 (Ki = 5.2 ± 0.3nM) receptors, with a slight selectivity for the latter. JWH-369 was first synthesized in 2006 by John W. Huffman and colleagues to examine the nature of ligand binding to the CB1 receptor.

References

  1. Lange JH, Coolen HK, van Stuivenberg HH, Dijksman JA, Herremans AH, Ronken E, et al. (January 2004). "Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists". Journal of Medicinal Chemistry. 47 (3): 627–643. doi:10.1021/jm031019q. PMID   14736243.
  2. Need AB, Davis RJ, Alexander-Chacko JT, Eastwood B, Chernet E, Phebus LA, et al. (January 2006). "The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats". Psychopharmacology. 184 (1): 26–35. doi:10.1007/s00213-005-0234-x. PMID   16328376. S2CID   23402768.
  3. Lange JH, van Stuivenberg HH, Veerman W, Wals HC, Stork B, Coolen HK, et al. (November 2005). "Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity". Bioorganic & Medicinal Chemistry Letters. 15 (21): 4794–4798. doi:10.1016/j.bmcl.2005.07.054. PMID   16140010.
  4. Srivastava BK, Joharapurkar A, Raval S, Patel JZ, Soni R, Raval P, et al. (November 2007). "Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular modeling in the homology model". Journal of Medicinal Chemistry. 50 (24): 5951–5966. doi:10.1021/jm061490u. PMID   17979261.
  5. Srivastava BK, Soni R, Joharapurkar A, Sairam KV, Patel JZ, Goswami A, et al. (February 2008). "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". Bioorganic & Medicinal Chemistry Letters. 18 (3): 963–968. doi:10.1016/j.bmcl.2007.12.036. PMID   18207393.
  6. de Bruin NM, Prickaerts J, Lange JH, Akkerman S, Andriambeloson E, de Haan M, et al. (May 2010). "SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents". Neurobiology of Learning and Memory. 93 (4): 522–531. doi:10.1016/j.nlm.2010.01.010. PMID   20132903. S2CID   207261719.
  7. de Bruin NM, Lange JH, Kruse CG, Herremans AH, Schoffelmeer AN, van Drimmelen M, De Vries TJ (March 2011). "SLV330, a cannabinoid CB(1) receptor antagonist, attenuates ethanol and nicotine seeking and improves inhibitory response control in rats". Behavioural Brain Research. 217 (2): 408–415. doi:10.1016/j.bbr.2010.11.013. PMID   21074574. S2CID   205882042.
  8. Lange JH, Sanders HJ, van Rheenen J (2011). "An expedient atom-efficient synthesis of the cannabinoid CB1 receptor inverse agonist ibipinabant". Tetrahedron Letters. 52 (12): 1303–1305. doi:10.1016/j.tetlet.2011.01.068.