Nonsymmetric P2/P2‘ Cyclic Urea HIV Protease Inhibitors. Structure−Activity Relationship, Bioavailability, and Resistance Profile of Monoindazole-Substituted P2 Analogues

Abstract

Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).

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

“…De Lucca et al [14] reported structure-activity data of hexahydro-5,6-dihydroxy-1-(R-benzyl)-3-(indazole-5-ylmethyl)-4,7-bis-(phenyl-methyl)-2H-1,3-diazepin-2-one substituted non-symmetric cyclic urea (1) analogues. Different congeners were synthesized by varying 3rd and 4th position substituents on P2 benzyl ring aiming at the S2/S3 pocket of the receptor.…”

“…All the biological data were taken from De Lucca et al [14]. They reported [14] inhibition of HIVPR (K i ) measured by assaying the cleavage of a fluorescent peptide substrate using HPLC.…”

“…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].…”

“…QSAR studies were performed using the structureactivity data reported [14] for congeneric series of cyclic urea (1). In all the QSAR reported here, n is the number of data points, r is the correlation coefficient, s is the standard deviation, q is the quality of fit and calculated as described by Cramer et al [18], and the data within parentheses are for the 95% confidence intervals.…”

“…Our ongoing efforts to understand the difference in the binding pattern of HIVPI with the WT and mutant HIVPR using QSAR approach and to provide mechanistic insight are continued further. We report here the results of a recent study on hexahydro-5,6-dihydroxy-1-(R-benzyl)-3-(indazole-5-yl-methyl)-4,7-bis-(phenyl-methyl)-2H-1,3-diazepin-2-one substituted non-symmetric analogues of cyclic urea (1) [14]. The QSAR models revealed an inverted parabolic relationship between biological activity and calculated molar refractivity (CMR) of the molecules.…”