title: Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.
abstract: Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.
authors.affiliation: Departments of Medicinal Chemistry and Biosciences, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA. boyer@mbasis.com
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: Hongjian
authors.initials: H
authors.lastname: Jiang
authors.forename: Jason D
authors.initials: JD
authors.lastname: Jacintho
authors.forename: Mali Venkat
authors.initials: MV
authors.lastname: Reddy
authors.forename: Haiqing
authors.initials: H
authors.lastname: Li
authors.forename: Wenyu
authors.initials: W
authors.lastname: Li
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Godwin
authors.forename: William G
authors.initials: WG
authors.lastname: Schulz
authors.forename: Edward E
authors.initials: EE
authors.lastname: Cable
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Hou
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.forename: James M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C539547:2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl)-4-(3-chlorophenyl)-2-oxido(1,3,2)dioxaphosphonane; D008024:Ligands; D063065:Organophosphonates; D011355:Prodrugs; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol; D005993:Glycerolphosphate Dehydrogenase