Structural determinants of selective thyromimetics.

Article Details

Citation

Yoshihara HA, Apriletti JW, Baxter JD, Scanlan TS

Structural determinants of selective thyromimetics.

J Med Chem. 2003 Jul 3;46(14):3152-61.

PubMed ID
12825953 [ View in PubMed
]
Abstract

The thyromimetic GC-1 shows a preference for binding the beta form of the thyroid hormone receptor (TR). GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an l-alanine polar side chain. The structural features of GC-1 that confer its greater affinity and selectivity compared to DIMIT were analyzed with the preparation of analogues that bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has selectivity comparable to that of GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TR-beta selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
LiothyronineThyroid hormone receptor alphaKd (nM)0.06N/AN/ADetails
LiothyronineThyroid hormone receptor betaKd (nM)0.087N/AN/ADetails
SobetiromeThyroid hormone receptor betaKd (nM)0.1N/AN/ADetails