The bicyclic isoindolin-5-ol (3) (Figure ) was the first analog to be prepared since it combined, in a single compound, the architecture of both the para-and meta-phenols using a simple atom count from the nitrogen to the oxygen (Figure ). In the ERa assays, isoindolin-5-ol (3) showed activity intermediate between 1 and 2 (Table ). In the LiSA, isoindolin-5-ol (3) was ~10-fold weaker than the para-phenol (1) but was 2-fold better than the meta-phenol (2). The cocrystal structure of 3 with ERa LBD (Figure ) revealed a binding mode in which the isoindolin-5-ol formed the full network of hydrogen bonds with E353, R394, and the water molecule that mimicked the steroidal hormone E2. An overlay of the X-ray structures of para-phenol (1), metaphenol (2), and isoindolin-5-ol (3) (Figure ) showed that three thieno [2,3-d]pyrimidines had an RMSD = 0.183 Å with the only difference in the ligands being the positioning of the OH of the para-phenol (1). For isoindolin-5-ol (3) there appeared to be no steric penalty to adoption of a rotamer that placed its OH in the same orientation as the para-phenol (1). Thus, the preference for isoindolin-5-ol (3) to bind the receptor in its crystallographically observed orientation must be due to some other factor.