Yonggang Wei

Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics

A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds 1, 2, and 6 were selected as potential candidates for further preclinical development including studies of their water-soluble prodrugs. Clinical studies of candidate compound 6 (Haisco HSK3486) as a general anesthetic are being performed in Australia and China.

Oral Delivery of Propofol with Methoxymethylphosphonic Acid as the Delivery Vehicle

Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.

Design, Synthesis, and Evaluation of a Series of Novel Benzocyclobutene Derivatives as General Anesthetics

In the present work, a series of structurally novel benzocyclobutene derivatives were identified as general anesthetics through the loss of righting reflex (LORR) experiment on mice. Our initial efforts found compound 1a with a fused four-membered ring on the 2,3-position of the phenol ring could significantly improve the safety profile. Further SAR study revealed that small hydrogen bond acceptor (HBA) groups are optimal for good ED50 along with much broader therapeutic windows, such as compounds 16b and 17. Present work demonstrates the superiority of this novel benzocyclobutene scaffold.