Structural determinants of selective thyromimetics

Hikari A.I. Yoshihara, James W. Apriletti, John D. Baxter, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The thyromimetic GC-1 shows a preference for binding the β 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-β selectivity.

Original languageEnglish (US)
Pages (from-to)3152-3161
Number of pages10
JournalJournal of Medicinal Chemistry
Volume46
Issue number14
DOIs
StatePublished - Jul 3 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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