Structure-Permeability Relationship of Semipeptidic Macrocycles-Understanding and Optimizing Passive Permeability and Efflux Ratio.

Autor: Le Roux A; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Blaise É; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Boudreault PL; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Comeau C; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Doucet A; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Giarrusso M; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada., Collin MP; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Neubauer T; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Kölling F; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Göller AH; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Seep L; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Tshitenge DT; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Wittwer M; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Kullmann M; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Hillisch A; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Mittendorf J; Drug Discovery, Pharmaceuticals, Bayer AG, Wuppertal D-42096, Germany., Marsault E; Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 Jul 09; Vol. 63 (13), pp. 6774-6783. Date of Electronic Publication: 2020 May 26.
DOI: 10.1021/acs.jmedchem.0c00013
Abstrakt: We herein report the first thorough analysis of the structure-permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure-permeability and structure-efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.
Databáze: MEDLINE
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