Cyclic HIV Protease Inhibitors:  Synthesis, Conformational Analysis, P2/P2‘ Structure−Activity Relationship, and Molecular Recognition of Cyclic Ureas

Abstract

High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure−activity relationships of C 2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry. The X-ray and solution NMR structure of the complex of HIV-1PR and one such cyclic urea, DMP323, confirmed the displacement of the structural water. Additionally, the bound and “unbound” (small-molecule X-ray) ligands have similar conformations. The high degree of preorganization, the complementarity, and the entropic gain of water displacement are proposed to explain the high affinity of these small molecules for the enzyme. The small size probably contributes to the observed good oral bioavailability in animals. Extensive structure-based optimization of the side chains that fill the S2 and S2‘ pockets of the enzyme resulted in DMP323, which was studied in phase I clinical trials but found to suffer from variable pharmacokinetics in man. This report details the synthesis, conformational analysis, structure−activity relationships, and molecular recognition of this series of C 2-symmetry HIV-1PR inhibitors. An initial series of cyclic ureas containing nonsymmetric P2/P2‘ is also discussed.

Computational design of novel cyclic urea as HIV-1 protease inhibitor

“…The ADME properties of cyclic urea chosen from literature [18][19][20][21][22][23][24] (structures shown in Figure 1) with varied range of inhibition constants were calculated. The ADME properties showed poor bioavailability.…”

Possible allosteric interactions of monoindazole-substituted P2 cyclic urea analogues with wild-type and mutant HIV-1 protease

“…They reported [14] inhibition of HIVPR (K i ) measured by assaying the cleavage of a fluorescent peptide substrate using HPLC. The antiviral potency (IC 90 ) of molecules as reported [14] was assessed by measuring their effect on the accumulation of viral RNA transcripts 3 days after infection of MT-2 cells with HIV-1 RF [17].…”

New anti‐HIV agents and targets

“…This has prompted the search for new, non-peptidic inhibitors of HIV protease, that in addition to a broader anti-HIV activity spectrum, might also offer increased oral bioavailability and/ or pharmacokinetic properties. Examples of non-peptidic protease inhibitors of HIV protease include 4-hydroxycoumarins and 4-hydroxy-2-pyrones, 171 sulfonamide-substituted derivatives, 172 cyclic ureas (i.e., DMP-323 and DMP-450), 173,174 cyclic cyanoguanidines, 175 aza-dipeptide analogues, 176 and tipranavir (PNU-140690), a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone. [177][178][179] The major advantage of the cyclic urea mozenavir (DMP-450) (35) is its substantial oral bioavailability observed in all species examined, including man.…”