HIV-1 protease inhibitors with a tertiary alcohol containing transition-state mimic and various P2 and P1′ substituents

Abstract

Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as the transition-state mimic have been synthesised and evaluated. Replacement of the previously used, but metabolically unstable, indanol amide group with amino acid derived aliphatic P2-P3 moieties provided potent inhibitors with low K i -and EC 50 -values (2.7 nM and 2.0 mM, respectively). The P1 0 subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing the corresponding inhibitors with retained activity. Permeability and stability studies showed examples in the same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes (9a and 9d) supplied detailed structural information. The binding modes were compared to those of Atazanavir and a previously reported indanol amide containing inhibitor ( 14). The novel inhibitors with an elongated P1 0 side chain enabled a previously unexploited edge-on interaction with Phe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2-P3 side chain, furnished small main chain displacements in the S2-S3 pocket. The methyl amide in the P3 position caused a 2 A shift of the Arg8/108 in comparison to 14, indicating the flexibility of the protease active site.

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…131 A tertiary chiral alcohol was investigated as the transition state mimetic. Modified derivatives were examined as the P1’ ligand.…”

“…This was observed when the carbon chain length was three and the P1’ substituents were 4-phenyl phenylalanine and 4-(3-thiophene)phenyl alanine as described by the co-crystal structure. 131 …”

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

“…In addition, the HIV‐1 PR is a well‐known enzyme since numerous investigations on this protein have been performed. The mechanism of the inhibitors preventing HIV‐1 PR is clarified in several previous studies using both experiments and computations . This enzyme becomes a favored target to develop a new method for prediction binding affinity.…”

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

“…There was no major difference between the 13 and the 19 series with respect to Cl int and P app , and the rigidification of the backbone seemed to be well tolerated compared to the linear inhibitors. 23 , 27 , 28 The metabolic stability was improved when the bromo group in 13a and 19a was substituted by the heteroaromatic pyridyls, although the permeability was unfortunately reduced at the same time.…”

“…The prepared tert -hydroxy comprising PIs rendered good affinity and potency. 23 − 28 Class B , with the two-carbon spacer, yielded the best results, with values of K i and EC 50 as low as 1 and 3 nM, respectively. 26 In all three series ( A – C ), inhibitors with high membrane permeability were identified, as well as inhibitors with good metabolic stability, 23 − 28 providing pharmacokinetic properties well in the range of HIV PIs already on the market, e.g., ATZ.…”