Several tissue-specific and TR isoform-specific compounds have been developed as potential treatments for hypercholesterolemia, obesity, and heart failure. An early prototypical compound was 3,5-dibromo-3-pyridazinone-L-thyronine (L-940901) which bound preferentially to the TRs in the liver over those in the heart . Although the relative affinity of this compound for the respective TR isoforms has not been reported, the selective action of L-940901 is likely due to tissue-specific uptake of the compound. Interestingly, mice treated with L-940901 had decreased serum cholesterol levels without cardiotoxicity. Recently, several other TH analogs have been described that have isoform-selective affinity for TRβ  compared to TRα . Since TRs in the liver are approximately 90% TRβ , and in the heart are mostly TRα , these isoform-selective compounds may serve as novel agents to lower serum cholesterol with minimal cardiotoxicity . N-[3,5-dimethyl-4-(4’-hydroxy-3’isopropylphenoxy)-phenyl]-oxamic acid (CGS 23425), 3,5-dimethyl-4(4’-hydroxy-3’-isopropylbenzyl)-phenoxy) acetic acid (GC-1), and 3,5-dichloro-4[(4-hydroxy-3-isoopropylphenoxy)phenyl] acetic acid (KB-141) all have been reported to lower total serum cholesterol and LDL-cholesterol . CGS 23425 also increases LDL receptor expression in HepG2 cells . Additionally, these compounds can increase serum apoA1 levels; however, the total serum high density lipoprotein (HDL) cholesterol level does not changes or may even decrease. In this connection, GC-1 decreased serum HDL; increased expression of HDL receptor, SR-B1; stimulated the activity of cholesterol 7α hydroxylase; and increased fecal excretion of bile acids in treated mice . Thus, GC-1 regulates important steps in the reverse cholesterol transport pathway. Recently, KB141 was shown to be a potential treatment for obesity by decreasing body weight via stimulation of metabolic rate and oxygen consumption .

TH analogs and derivatives also bind specifically to proteins other than TRs, and are involved in non-genomic cell signaling pathways. Recently, Scanlan and colleagues identified 3-iodothyronamine (T1AM), which is a naturally occurring byproduct of TH, as a potent agonist of the G protein-coupled trace amine receptor, TAR1 . Significantly, this compound bound poorly to nuclear TRs. T1AM has interesting physiological actions as it produced a rapid drop in body temperature and heart rate when injected intraperitoneally in mice. T1AM also decreased cardiac output in an ex vivo working heart model. These physiological actions of T1AM are opposite of those observed for T3, and may provide a counter-regulation to the transcriptional effects of TH by nuclear TRs.

TH can increase cardiac performance by increasing cardiac contractility and decreasing systemic vascular resistance ; however, TH excess also can cause cardiotoxicity. 3,5-diiodothyropropionic acid (DITPA) is a TH-related compound with low metabolic activity and low affinity for nuclear TRs (Kd 10-7M) . DITPA was able to increase cardiac contractility and peripheral circulation without significant effects on heart rate in animal studies. Moreover, DITPA improved hemodynamic performance in animal models of congestive heart failure after myocardial infarction. Patients with heart failure treated with DITPA showed significant improvement in systolic cardiac index and systemic vascular resistance in preliminary studies . Thus DITPA or similar compounds may represent a novel class of drugs for the treatment of heart failure.