Cagrilintide

Last updated

Cagrilintide
Cagrilintide.png
Clinical data
Other namesGLXC-26801
ATC code
  • None
Identifiers
  • 20-[[(1S)-4-[[(2S)-6-amino-1-[[(4R,7S,10S,13S,16S,19R)-4-[[(2S)-1-[[(2S,3R)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2R)-4-amino-1-[[(2S)-1-[[2-[(2S)-2-[[(2S,3S)-1-[[(2S)-1-[(2S)-2-[(2S)-2-[[(2S,3R)-1-[[(2S)-4-amino-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-4-amino-1-[[(2S,3R)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]-16-(2-amino-2-oxoethyl)-7,13-bis[(1R)-1-hydroxyethyl]-10-methyl-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxohexan-2-yl]amino]-1-carboxy-4-oxobutyl]amino]-20-oxoicosanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
Chemical and physical data
3D model (JSmol)
  • CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N3CCC[C@H]3C(=O)N)NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](CC5=CC=CC=C5)NC(=O)[C@@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC6=CNC=N6)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC7=CC=CC=C7)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@@H]8CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N8)[C@@H](C)O)C)[C@@H](C)O)CC(=O)N)NC(=O)[C@H](CCCCN)NC(=O)CC[C@@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O
  • InChI=1S/C194H312N54O59S2/c1-19-100(10)151(184(298)233-128(78-98(6)7)189(303)248-75-49-60-137(248)190(304)247-74-48-59-136(247)182(296)243-155(107(17)255)187(301)232-127(86-143(201)262)173(287)238-150(99(8)9)183(297)210-88-146(265)218-129(90-249)176(290)230-126(85-142(200)261)175(289)244-156(108(18)256)191(305)246-73-46-57-134(246)157(202)271)239-181(295)135-58-47-72-245(135)147(266)89-211-161(275)120(79-109-50-36-34-37-51-109)225-171(285)123(82-139(197)258)228-172(286)124(83-140(198)259)229-177(291)130(91-250)235-178(292)131(92-251)234-170(284)122(81-111-87-207-95-212-111)227-164(278)114(56-45-71-209-194(205)206)221-168(282)119(77-97(4)5)224-169(283)121(80-110-52-38-35-39-53-110)226-166(280)116(65-68-149(269)270)219-158(272)101(11)213-167(281)118(76-96(2)3)223-163(277)113(55-44-70-208-193(203)204)220-165(279)115(63-66-138(196)257)222-186(300)153(105(15)253)240-159(273)102(12)214-179(293)132-93-308-309-94-133(180(294)231-125(84-141(199)260)174(288)242-152(104(14)252)185(299)215-103(13)160(274)241-154(106(16)254)188(302)237-132)236-162(276)112(54-42-43-69-195)216-145(264)67-64-117(192(306)307)217-144(263)61-40-32-30-28-26-24-22-20-21-23-25-27-29-31-33-41-62-148(267)268/h34-39,50-53,87,95-108,112-137,150-156,249-256H,19-33,40-49,54-86,88-94,195H2,1-18H3,(H2,196,257)(H2,197,258)(H2,198,259)(H2,199,260)(H2,200,261)(H2,201,262)(H2,202,271)(H,207,212)(H,210,297)(H,211,275)(H,213,281)(H,214,293)(H,215,299)(H,216,264)(H,217,263)(H,218,265)(H,219,272)(H,220,279)(H,221,282)(H,222,300)(H,223,277)(H,224,283)(H,225,285)(H,226,280)(H,227,278)(H,228,286)(H,229,291)(H,230,290)(H,231,294)(H,232,301)(H,233,298)(H,234,284)(H,235,292)(H,236,276)(H,237,302)(H,238,287)(H,239,295)(H,240,273)(H,241,274)(H,242,288)(H,243,296)(H,244,289)(H,267,268)(H,269,270)(H,306,307)(H4,203,204,208)(H4,205,206,209)/t100-,101-,102-,103-,104+,105+,106+,107+,108+,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123+,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,150-,151-,152-,153-,154-,155-,156-/m0/s1
  • Key:LDERDVMBIYGIOI-DDPFBLHVSA-N

Cagrilintide is a long-acting analogue of amylin. It is being tested to treat obesity and type 2 diabetes by itself and in combination with semaglutide as cagrilintide/semaglutide. [1] [2] [3] [4] [5] [6]

Research

A systematic review and metanalysis of cagrisema, published in 2024, found that cagrisema may provide weight loss benefits. [7]

Related Research Articles

Satiety is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. Following satiation, satiety is a feeling of fullness lasting until the next meal. When food is present in the GI tract after a meal, satiety signals overrule hunger signals, but satiety slowly fades as hunger increases.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

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

Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was first-in-class for clinical development.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Calcitonin receptor</span> Protein found in humans

The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism.

<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 developed by Merck & Co.

<span class="mw-page-title-main">Lorcaserin</span> Antiobesity drug

Lorcaserin, marketed under the brand name Belviq, was a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating serotonin receptor the 5-HT2C receptor in the hypothalamus, a region of the brain which is known to control appetite. It was approved in 2012, and in 2020, it was removed from the market in the United States due to an increased risk of cancer detected in users of Belviq.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

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

Telcagepant (INN) is a calcitonin gene-related peptide receptor antagonist which was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co.

<span class="mw-page-title-main">EMA401</span> Chemical compound

EMA401 is a drug under development for the treatment of peripheral neuropathic pain. Trials were discontinued in 2015, with new trials scheduled to begin March, 2018. It was initially established as a potential drug option for patients suffering pain caused by postherpetic neuralgia. It may also be useful for treating various types of chronic neuropathic pain EMA401 has shown efficacy in preclinical models of shingles, diabetes, osteoarthritis, HIV and chemotherapy. EMA401 is a competitive antagonist of angiotensin II type 2 receptor (AT2R) being developed by the Australian biotechnology company Spinifex Pharmaceuticals. EMA401 target angiotensin II type 2 receptors, which may have importance for painful sensitisation.

<span class="mw-page-title-main">Semaglutide</span> Anti-diabetic and anti-obesity medication

Semaglutide is an anti-diabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold by Novo Nordisk under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic and weight loss medication

Tirzepatide is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections. It is sold under the brand name Mounjaro for diabetes treatment, and Zepbound for weight loss and treatment of obstructive sleep apnea.

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

Orforglipron (LY-3502970) is an oral, non-peptide, small molecule glucagon-like peptide-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company. It is easier to produce than current peptide GLP-1 agonists and is expected to be cheaper.

Cagrilintide/semaglutide, marketed as CagriSema, is a combination of cagrilintide, a dual amylin and calcitonin receptor agonist, and semaglutide, a GLP-1 agonist. It is injected once weekly and is being tested in type 2 diabetes and obesity. Preliminary trial results found a greater weight loss compared to either medication alone. HbA1c was significantly improved compared to cagrilintide alone and non-significantly better than semaglutide alone. In a Phase II trial, weight loss averaged -15.6 percent after 32 weeks, making CagriSema comparable in efficacy to tirzepatide. A future trial sponsored by Novo Nordisk is comparing tirzepatide and CagriSema head-to-head. As of 2023, CagriSema is in a Phase III trial.

The amylin receptors (AMYRs) are heterodimers of the calcitonin receptor that are bound to by amylin with high affinity and consist of AMY1, AMY2, and AMY3. Amylin mimetics that are agonists at the amylin receptors are being developed as therapies for diabetes and obesity, and one, pramlintide, has been FDA approved. The AMY1 receptor may be activated by both amylin and the calcitonin gene-related peptide (CGRP) and could play a role in the effects of CGRP receptor antagonists developed for migraine. Dual agonists of the amylin and calcitonin receptors (DACRAs) are under development for obesity. Amylin and its receptors are believed to play a role in Alzheimer's disease.

Dual amylin and calcitonin receptor agonists (DACRAs) are a class of drugs that act as agonists at the amylin receptor and calcitonin receptor that are under development as therapies for obesity and type 2 diabetes. Examples are cagrilintide, Petrelintide, ACCG-2671 and the KBP family derived from salmon calcitonin, including KBP‐042, KBP-066A, KBP-089, and KBP-336.

Petrelintide is an amylin analogue dosed once weekly, developed by Zealand Pharma for the treatment of type 2 diabetes and obesity. Preclinical data suggests it may be more effective in combination with semaglutide. In June 2024 the company announced results for a Phase 1b trial, which found 8.6 percent weight loss over 16 weeks.

Mazdutide is a dual agonist of the GLP-1 receptor and glucagon receptor. It is an analog of oxyntomodulin (OXM). The drug is developed by Eli Lilly and is currently in multiple Phase III studies.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

References

  1. ↑ Larsen, Anna T.; Sonne, Nina; Mohamed, Khaled Elhady; Bredtoft, Emma-Marie; Andersen, Frederik; Karsdal, Morten A.; et al. (1 June 2022). "823-P: The Long-Acting Dual Amylin and Calcitonin Receptor Agonist KBP Has Increased Efficacy on Weight Loss and Glucose Control Compared with Cagrilintide in Obese and Diabetic Rats". Diabetes. 71 (Supplement_1). doi:10.2337/db22-823-P. S2CID   249259033.
  2. ↑ Lau, David C W; Erichsen, Lars; Francisco, Ann Marie; Satylganova, Altynai; le Roux, Carel W; McGowan, Barbara; et al. (December 2021). "Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial". The Lancet. 398 (10317): 2160–2172. doi:10.1016/S0140-6736(21)01751-7. PMID   34798060. S2CID   244169045.
  3. ↑ Kruse, Thomas; Hansen, Jakob Lerche; Dahl, Kirsten; Schäffer, Lauge; Sensfuss, Ulrich; Poulsen, Christian; et al. (12 August 2021). "Development of Cagrilintide, a Long-Acting Amylin Analogue". Journal of Medicinal Chemistry. 64 (15): 11183–11194. doi: 10.1021/acs.jmedchem.1c00565 . ISSN   0022-2623. PMID   34288673. S2CID   236175929.
  4. ↑ Frias, Juan P; Deenadayalan, Srikanth; Erichsen, Lars; Knop, Filip K; Lingvay, Ildiko; Macura, Stanislava; et al. (August 2023). "Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial". The Lancet. 402 (10403): 720–730. doi:10.1016/S0140-6736(23)01163-7. PMID   37364590. S2CID   259237278.
  5. ↑ D’Ascanio, Antonella M.; Mullally, Jamie A.; Frishman, William H. (8 March 2023). "Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity". Cardiology in Review (Publish Ahead of Print). doi:10.1097/CRD.0000000000000513. PMID   36883831. S2CID   257404657.
  6. ↑ Larsen, A. T.; Mohamed, K. E.; Sonne, N.; Bredtoft, E.; Andersen, F.; Karsdal, MA; et al. (1 December 2022). "Does receptor balance matter? – Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models". Biomedicine & Pharmacotherapy. 156: 113842. doi: 10.1016/j.biopha.2022.113842 . ISSN   0753-3322. PMID   36242844. S2CID   252881350.
  7. ↑ Dutta D, Nagendra L, Harish BG, Sharma M, Joshi A, Hathur B, et al. (2024). "Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (Cagrisema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis". Indian Journal of Endocrinology and Metabolism. 28 (5): 436–444. doi: 10.4103/ijem.ijem_45_24 . PMC   11642503 . PMID   39676787.


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