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Pramlintide

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Pramlintide
Golden line indicatesdisulfidebond
Clinical data
Trade namesSymlin
AHFS/Drugs.comMonograph
MedlinePlusa605031
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability30 to 40%
Protein binding~60%
MetabolismRenal
Eliminationhalf-life~48 minutes
Identifiers
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC171H267N51O53S2
Molar mass3949.44g·mol−1
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)N[C@@H](Cc3ccc(cc3)O)C(=O)N)NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](Cc5ccccc5)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](Cc6cnc[nH]6)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc7ccccc7)NC(=O)[C@H](CC(=O)N)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)N
  • InChI=1S/C171H267N51O53S2/c1-21-81(12)130(163(268)207-110(56-78(6)7)169(274)222-53-33-42-118(222)170(275)221-52-32-41-117(221)160(265)219-135(89(20)230)167(272)206-109(66-125(180)238)151(256)212-128(79(8)9)161(266)186-68-126(239)192-111(70-223)154(259)203-107(64-123(178)236)152(257)218-134(88(19)229)166(271)195-98(136(181)241)57-92-43-45-94(231)46-44-92)214-159(264)116-40-31-51-220(116)127(240)69-187-141(246)101(58-90-34-24-22-25-35-90)199-148(253)105(62-121(176)234)201-149(254)106(63-122(177)235)202-155(260)112(71-224)209-156(261)113(72-225)208-146(251)103(60-93-67-184-75-188-93)205-162(267)129(80(10)11)213-150(255)100(55-77(4)5)198-145(250)102(59-91-36-26-23-27-37-91)200-147(252)104(61-120(175)233)196-137(242)82(13)189-144(249)99(54-76(2)3)197-142(247)96(39-30-50-185-171(182)183)193-143(248)97(47-48-119(174)232)194-165(270)132(86(17)227)215-138(243)83(14)190-157(262)114-73-276-277-74-115(210-140(245)95(173)38-28-29-49-172)158(263)204-108(65-124(179)237)153(258)217-131(85(16)226)164(269)191-84(15)139(244)216-133(87(18)228)168(273)211-114/h22-27,34-37,43-46,67,75-89,95-118,128-135,223-231H,21,28-33,38-42,47-66,68-74,172-173H2,1-20H3,(H2,174,232)(H2,175,233)(H2,176,234)(H2,177,235)(H2,178,236)(H2,179,237)(H2,180,238)(H2,181,241)(H,184,188)(H,186,266)(H,187,246)(H,189,249)(H,190,262)(H,191,269)(H,192,239)(H,193,248)(H,194,270)(H,195,271)(H,196,242)(H,197,247)(H,198,250)(H,199,253)(H,200,252)(H,201,254)(H,202,260)(H,203,259)(H,204,263)(H,205,267)(H,206,272)(H,207,268)(H,208,251)(H,209,261)(H,210,245)(H,211,273)(H,212,256)(H,213,255)(H,214,264)(H,215,243)(H,216,244)(H,217,258)(H,218,257)(H,219,265)(H4,182,183,185)/t81-,82-,83-,84-,85+,86+,87+,88+,89+,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,128-,129-,130-,131-,132-,133-,134-,135-/m0/s1☒N
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Pramlintide(trade nameSymlin) is an injectableamylinanalogue drug fordiabetes(both type 1 and 2), developed byAmylin Pharmaceuticals(now a wholly owned subsidiary ofAstraZeneca).[1]Pramlintide is sold as an acetate salt.

Pharmacology

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Pramlintide is an analogue ofamylin,a small peptidehormonethat is released into thebloodstreamby theβ cellsof thepancreasalong withinsulinafter a meal.[2]Like insulin, amylin is completely absent in individuals with Type I diabetes.[3]

In synergy with endogenous amylin, pramlintide aids in the regulation of bloodglucoseby slowinggastric emptying,promotingsatietyviahypothalamicreceptors (different receptors than forGLP-1), and inhibiting inappropriate secretion ofglucagon,a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.[citation needed]

Both a reduction inglycated hemoglobinand weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.[4]

Research Applications

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In the research field, pramlintide has been experimented with and used as a potential treatment drug. Pramlintide has demonstrated its ability to decreaseamyloid betaplaques inAlzheimer's diseasemouse models.[5]

Approval

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Pramlintide has been approved on 3/16/2005 by the FDA, for use by type 1 and type 2 diabetic patients who use insulin.[6](subscription required)Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating.

Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.[citation needed][7]

Design and structure

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Since native human amylin is highlyamyloidogenicand potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is less amyloidogenic[8][9]but presumably retains clinical activity. Proline residues are known to be structure-breaking[clarification needed]residues, so these were directly grafted into the human sequence. Despite its enhanced stability compared to human amylin, however, pramlintide is still able to organize into amyloid material.[10]

Amino acid sequences:

Pramlintide KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-(NH2)
Amylin KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-(NH2)
Rat amylin KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-(NH2)

Pramlintide is apositively chargedprotein.[citation needed]

References

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  1. ^Taylor P (19 December 2013)."AstraZeneca buys BMS out of diabetes alliance".Retrieved16 June2014.
  2. ^Jones MC (June 2007)."Therapies for diabetes: pramlintide and exenatide"(PDF).American Family Physician.75(12): 1831–1835.PMID17619527.
  3. ^Edelman S, Maier H, Wilhelm K (2008). "Pramlintide in the treatment of diabetes mellitus".BioDrugs.22(6): 375–386.doi:10.2165/0063030-200822060-00004.PMID18998755.S2CID34608423.
  4. ^Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG, Weyer C (April 2004)."Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients".Obesity Research.12(4): 661–668.doi:10.1038/oby.2004.76.PMID15090634.
  5. ^Tao Q, Zhu H, Chen X, Stern RA, Kowall N, Au R, et al. (2018)."Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease".Journal of Alzheimer's Disease.62(2): 597–609.doi:10.3233/jad-170948.PMC5956916.PMID29480193.
  6. ^Ryan GJ, Jobe LJ, Martin R (October 2005). "Pramlintide in the treatment of type 1 and type 2 diabetes mellitus".Clinical Therapeutics.27(10): 1500–1512.doi:10.1016/j.clinthera.2005.10.009.PMID16330288.
  7. ^"Dual-Hormone, Artificial Pancreas with Insulin and Pramlintide Significantly Improves Glucose Levels, Compared to Insulin-Only Artificial Pancreas".American Diabetes Association.Archived fromthe originalon 2018-08-29.Retrieved2018-08-28.
  8. ^Palmieri LC, Melo-Ferreira B, Braga CA, Fontes GN, Mattos LJ, Lima LM (2013). "Stepwise oligomerization of murine amylin and assembly of amyloid fibrils".Biophysical Chemistry.180–181: 135–144.doi:10.1016/j.bpc.2013.07.013.PMID23974296.
  9. ^Erthal LC, Marques AF, Almeida FC, Melo GL, Carvalho CM, Palmieri LC, et al. (November 2016). "Regulation of the assembly and amyloid aggregation of murine amylin by zinc".Biophysical Chemistry.218:58–70.doi:10.1016/j.bpc.2016.09.008.PMID27693831.
  10. ^da Silva DC, Fontes GN, Erthal LC, Lima LM (December 2016). "Amyloidogenesis of the amylin analogue pramlintide".Biophysical Chemistry.219:1–8.doi:10.1016/j.bpc.2016.09.007.PMID27665170.
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