Stereoisomers of cyclic urea HIV-1 protease inhibitors: synthesis and binding affinities.

We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino acid starting materials was used to prepare three isomers. Three additional isomers were prepared by synthetic routes utilizing L-tartaric acid and D-sorbitol as chiral starting materials. A stereoselective hydroxyl inversion of the cyclic urea trans-diol was used to prepare three additional isomers. In all 9 of the 10 possible cyclic urea stereoisomers were prepared, and their binding affinities are described.

The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors.

Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.

Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.

Preparation and structure-activity relationship of novel P1/P1'-substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors.

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

Synthesis of novel cyclic urea based HIV-1 protease inhibitors.

A series of novel HIV-1 protease inhibitors was prepared in a short stereospecific manner. These compounds have only one P1 substituent interacting with the S1/S1' binding site of HIV-1 protease and only one hydroxyl group interacting with the catalytic aspartic acid domain, X-ray crystallography confirmed the desired R, R configuration of the final products.

An approach to the design of novel cognitive enhancers using molecular modeling and X-ray crystallography.

A novel series of cognition enhancers was designed based on molecular modeling and X-ray structure analysis of EXP-9121 (2). This new series features a spirocyclic ring system that constrains the side chain substituents into the orientation seen in the X-ray crystal structure of 2. MM2 calculations preformed on 2 accurately predicted the solid state conformation. Compounds could be rapidly assembled using a bis-Michael addition reaction. Unfortunately, in vitro testing showed moderate activity at best, suggesting the X-ray structure of 2 does not mimic the bioactive conformation.