Author/Authors :
Jon J. Hangeland، نويسنده , , Arthur M. Doweyko، نويسنده , , Tamara Dejneka، نويسنده , , Todd J. Friends، نويسنده , , Pratik Devasthale، نويسنده , , Karin Mellstr?m، نويسنده , , Johnny Sandberg، نويسنده , , Marlena Grynfarb، نويسنده , , John S. Sack، نويسنده , , Howard Einspahr، نويسنده , , Mathias F?rneg?rdh، نويسنده , , Bolette Husman، نويسنده , , Jan Ljunggren، نويسنده , , Konrad Koehler، نويسنده , , Cheryl Sheppard، نويسنده , , Johan Malm، نويسنده , , Denis E. Ryono، نويسنده ,
Abstract :
A set of thyromimetics having improved selectivity for TR-β1 were prepared by replacing the 3′-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3′-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-β1 LBD shows methionine 442 to be displaced by the bulky R3′ phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand–receptor complex retains full agonist activity.
Keywords :
Thyromimetics , Thyroid hormone receptor.* Corresponding author. Tel.: +1-609-818-4958 , e-mail: jon.hangeland@bms.com , fax: +1-609-818-3450
