title: Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability.
abstract: The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Vincent
authors.initials: V
authors.lastname: Andersson
authors.affiliation: CVMD iMed DMPK, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bergström
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Brånalt
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Grönberg
authors.affiliation: Emeriti Pharma AB, AZ Bioventure Hub, c/o AstraZeneca , S-431 83 Mölndal, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Karlsson
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Polla
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Department of Chemistry-BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047028:Macrocyclic Compounds; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors; D013917:Thrombin