Synthesis of MK-2048: A tricyclic hydroxypyrrole HIV-1 integrase strand transfer inhibitor with unique resistance properties

ORGN 657

Mark W. Embrey, mark_embrey@merck.com1, Thorsten E. Fisher1, Terry A. Lyle1, Joseph P. Vacca, joe_vacca@merck.com1, Daria J. Hazuda2, Michael D. Miller2, Peter J. Felock2, Marc V. Witmer2, Lori J. Gabryelski3, and John S. Wai1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, (2) Department of Antiviral Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, (3) Department of Viral Vaccine Research, Merck Research Laboratories, West Point, PA 19486
A series of novel tricyclic 10-hydroxy-7, 8-dihydropyrazinopyrrolopyrazine-1, 9-dione HIV-1 integrase inhibitors was synthesized. These compounds selectively inhibit the stand transfer step of integration and are active against HIV-1 in cell culture. Further optimization led to inhibitors with excellent antiviral potency, a subset of which also retained activity against a panel of mutants raised in the laboratory with different integrase inhibitors. The lead compound, MK-2048 (IC95 41 nM in 50% NHS), exhibits good pharmacokinetics in dog and rat. Significantly, this compound also maintained excellent activity against the N155S and G140S/Q148H mutants that display substantial cross resistance to many structurally distinct integrase strand transfer inhibitors. A scaleable synthesis of MK-2048 will be presented, which includes an unprecedented asymmetric hydrogenation to the chiral piperazinone ring.

 

Technical Achievements in Organic Chemistry Award Symposium
9:00 AM-11:55 AM, Wednesday, August 22, 2007 BCEC -- 254 A/B, Oral

Division of Organic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007