Summary information and primary citation
- PDB-id
- 4ztf; DSSR-derived features in text and JSON formats
- Class
- transferase-DNA-inhibitor
- Method
- X-ray (2.7 Å)
- Summary
- Crystal structure of the prototype foamy virus intasome with a 2-pyridinone aminal inhibitor
- Reference
- Raheem IT, Walji AM, Klein D, Sanders JM, Powell DA, Abeywickrema P, Barbe G, Bennet A, Clas SD, Dubost D, Embrey M, Grobler J, Hafey MJ, Hartingh TJ, Hazuda DJ, Miller MD, Moore KP, Pajkovic N, Patel S, Rada V, Rearden P, Schreier JD, Sisko J, Steele TG, Truchon JF, Wai J, Xu M, Coleman PJ (2015): "Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors." J.Med.Chem., 58, 8154-8165. doi: 10.1021/acs.jmedchem.5b01037.
- Abstract
- The search for new molecular constructs that resemble the critical 2-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetics to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
