Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans.

Autor: Kjeldsen TB; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Hubálek F; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Hjørringgaard CU; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Tagmose TM; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Nishimura E; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Stidsen CE; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Porsgaard T; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Fledelius C; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Refsgaard HHF; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Gram-Nielsen S; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Naver H; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Pridal L; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Hoeg-Jensen T; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Jeppesen CB; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Manfè V; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Ludvigsen S; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Lautrup-Larsen I; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Madsen P; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Jul 08; Vol. 64 (13), pp. 8942-8950. Date of Electronic Publication: 2021 May 04.
DOI: 10.1021/acs.jmedchem.1c00257
Abstrakt: Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure-activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure-activity relationship study leading to insulin icodec is presented here.
Databáze: MEDLINE
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