retatrutide   Click here for help

GtoPdb Ligand ID: 13769

Compound class: Peptide
Comment: Retatrutide (LY3437943) is a triple peptidic agonist of the glucagon receptor (GCGR), glucosedependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R) [4]. This represents an example of intentional 'unimolecular polypharmacology' to achieve the desired therapeutic benefit(s). The peptide is lipidated and amino acids are modified to optimise pharmacokinetics and pharmacodynamics [1]. Retatrutide activates all 3 receptors in vitro, and binds more strongly to GIPR compared to the other two target receptors.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CC[C@H](C)C(C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N3CCC[C@H]3C(=O)N4CCC[C@H]4C(=O)N5CCC[C@H]5C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](CC6=CC=CC=C6)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)CC[C@@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@](C)(CC(C)C)NC(=O)C([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CC=C(C=C7)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC8=CC=CC=C8)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)C(C)(C)NC(=O)[C@H](CC9=CC=C(C=C9)O)N
Isomeric SMILES CC[C@H](C)C(C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N3CCC[C@H]3C(=O)N4CCC[C@H]4C(=O)N5CCC[C@H]5C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](CC6=CC=CC=C6)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)CC[C@@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@](C)(CC(C)C)NC(=O)C([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CC=C(C=C7)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC8=CC=CC=C8)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)C(C)(C)NC(=O)[C@H](CC9=CC=C(C=C9)O)N
InChI InChI=1S/C221H342N46O68/c1-23-124(11)179(208(322)241-144(83-88-176(291)292)192(306)245-150(105-134-69-75-137(276)76-70-134)196(310)244-148(100-121(5)6)194(308)243-147(99-120(3)4)193(307)240-142(82-87-175(289)290)187(301)230-110-169(282)229-113-173(286)264-92-51-61-161(264)206(320)253-158(116-270)203(317)251-157(115-269)189(303)232-111-170(283)233-128(15)212(326)266-94-53-63-163(266)214(328)267-95-54-64-164(267)213(327)265-93-52-62-162(265)207(321)250-156(114-268)183(226)297)258-200(314)152(103-131-55-41-39-42-56-131)242-185(299)127(14)235-216(331)219(18,19)262-205(319)145(80-85-166(225)279)237-184(298)126(13)234-190(304)140(60-48-50-90-227-172(285)119-335-98-97-334-96-91-228-167(280)86-81-146(215(329)330)236-168(281)65-45-37-35-33-31-29-27-25-26-28-30-32-34-36-38-46-66-174(287)288)238-191(305)141(59-47-49-89-222)239-198(312)154(107-177(293)294)247-195(309)149(101-122(7)8)256-218(333)221(22,109-123(9)10)263-211(325)180(125(12)24-2)259-204(318)160(118-272)252-197(311)151(106-135-71-77-138(277)78-72-135)246-199(313)155(108-178(295)296)248-202(316)159(117-271)254-210(324)182(130(17)274)260-201(315)153(104-132-57-43-40-44-58-132)249-209(323)181(129(16)273)257-171(284)112-231-188(302)143(79-84-165(224)278)255-217(332)220(20,21)261-186(300)139(223)102-133-67-73-136(275)74-68-133/h39-44,55-58,67-78,120-130,139-164,179-182,268-277H,23-38,45-54,59-66,79-119,222-223H2,1-22H3,(H2,224,278)(H2,225,279)(H2,226,297)(H,227,285)(H,228,280)(H,229,282)(H,230,301)(H,231,302)(H,232,303)(H,233,283)(H,234,304)(H,235,331)(H,236,281)(H,237,298)(H,238,305)(H,239,312)(H,240,307)(H,241,322)(H,242,299)(H,243,308)(H,244,310)(H,245,306)(H,246,313)(H,247,309)(H,248,316)(H,249,323)(H,250,321)(H,251,317)(H,252,311)(H,253,320)(H,254,324)(H,255,332)(H,256,333)(H,257,284)(H,258,314)(H,259,318)(H,260,315)(H,261,300)(H,262,319)(H,263,325)(H,287,288)(H,289,290)(H,291,292)(H,293,294)(H,295,296)(H,329,330)/t124-,125-,126-,127-,128-,129+,130+,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,179?,180?,181-,182-,221+/m0/s1
InChI Key MLOLQJNKXBNWFW-SAGGEDDASA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK et al.. (2022)
LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.
Cell Metab, 34 (9): 1234-1247.e9. [PMID:35985340]
2. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML et al.. (2023)
Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.
N Engl J Med, 389 (6): 514-526. [PMID:37366315]
3. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z et al.. (2023)
Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.
Lancet, 402 (10401): 529-544. [PMID:37385280]
4. Tetelbaun L, Mullally JA, Frishman WH. (2024)
The First Triple Agonist for Antiobesity: Retatrutide.
Cardiol Rev, [Epub ahead of print]. [PMID:39724554]