Bis Tertiary Amide Inhibitors of the HIV-1 Protease Generated via Protein Structure-Based Iterative Design

Abstract

A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.

Modeling Protein−Ligand Binding by Mining Minima

“… Experimental free energies sourced as follows: a 96 , b 97 , c 98 , d 99 , e 100 , f 101 , g 77,102,103 and BindingDB Entry 285, i 73 . Crystal structures as follows: j 1HPV 104 , k 1MUI 105 , l 1HXW 106 , m 1HPX 107 , n 1KZK 108 , o 2FDE 78 , p 1HVR 77 , q 2I0D 73 , r 2I0A 73 , s 3GI4 109 . …”

One‐Pot Sequential Schmidt and Ritter Reactions for the Synthesis of N‐tert‐Butyl Amides

“…Similarly, saquinavir, the first HIV protease inhibitor, is currently undergoing clinical evaluation and contains the N ‐ tert ‐butyl amide moiety 3. Moreover, Agouron Pharmaceuticals has recently synthesized some diarylbutanols4,5 that also bear the N ‐ tert ‐butyl amide moiety. These molecules are known to exhibit potent anti‐HIV protease activities as well.…”

New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

“…Although pepstatin A was found to be a potent inhibitor of the HIV-1 aspartyl protease, the peptidic nature of the inhibitor resulted in poor bioavailability [24]. In order to improve bioavailability and improve in vivo half-life, recent research has focused on smaller inhibitors that contain non-peptide functionalities in place of the peptide bond cleavage site of the substrate [25, 26]. …”

“…The use of hydroxyethyl isosteres with cyclic tertiary amines have led to compounds with enhanced oral absorption [25, 26]. Similarly, hydroxyethylamine isosteres have been used as potent inhibitors of the aspartyl protease plasmepsin [27, 28].…”