A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.

Adrenoceptors beta‐3‐subtype mediate lipolysis and in the search for potential beta‐3‐adrenergic receptors agonists for the treatment of obesity, we designed new arylethanolamines (structures 4, 5) and aryloxypropanolamines (structures 6, 7) derived from 2(3H)‐benzoxazolone and 2(3H)‐benzothiazolone.

Beta‐3‐subtype‐adrenoceptors mediate lipolysis and in the search for potential beta‐3‐adrenergic receptor agonists for the treatment of obesity, we designed new arylethanolamines, structures B1 and B2, derived from 2(3H)‐benzoxazolinone. To obtain these target compounds as starting materials, various N‐benzyl‐[2(3H)‐benzoxazolinon‐6‐yl]ethylamines were used.

Synthesis of 2(3H)-Benzoxazolinone Derivatives as Potential Beta-3-adrenergic Receptor Ligands.-In the search for potential beta-3adrenergic receptor antagonists for treatment of obesity, new arylethanolamines derived from benzoxazolinone, structures (VII) and (XI), are designed. -(DELHOMEL, J. F.; YOUS, S.; DEPREUX, P.; LESIEUR, D.; J. Heterocycl.

Synthesis of 2(3H)-Benzoxazolone and 2(3H)-Benzothiazolone Derivatives as Potential Beta-3-adrenergic Receptor Ligands. Part 2.-The benzoxazolone unit of a previously synthesized compound, bearing the acidic functionality, is replaced by a phenoxyacetic acid group to investigate the role of this moiety. Thus, the two benzoxazolinonic and benzothiazolinonic series of arylethanolamines (IX) and aryloxypropanolamines (XII) are designed and prepared as potential beta-3-adrenergic receptor agonists for the treatment of obesity. -(DELHOMEL, J. F.; YOUS, S.; DEPREUX, P.; LESIEUR, D.; J. Heterocycl. Chem. 38 (2001) 3, 633-639; Lab. Chim. Pharm., Fac. Sci. Pharm. Biol., F-59006 Lille, Fr.; EN)