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within the N-terminus of gp41, which through additional conforma-
tional rearrangements in gp41 facilitates fusion between the viral
and cellular membranes and release of the viral core into the cell.
Several groups are actively involved in the development of
small molecules targeted to gp120 that disrupt the Env molecular
machine to stop HIV-1 entry into cells.4–13 Despite this only one
chemotype, developed by Bristol Myers Squibb, has successfully
made it to clinical trials. The newest compound in the drug class,
BMS-663068, a phosphonooxymethyl prodrug of BMS-626529,14
recently performed favourably in a Phase IIb clinical study, high-
lighting the potential utility of these Env-directed entry inhibitor
class of compounds (presented at the 22nd Conference on Retro-
viruses and Opportunistic Infections [CROI]).
Our group recently described the computational design of new
compounds designed to act through a common binding site to that
of the Bristol Myers Squibb piperazine-based entry inhibitors, of
which BMS-663068/BMS626529 are members. Our most potent
compounds, SC11 and SC26, both contain a dipyrrolodine core
scaffold, and specifically inhibit HIV-1JR-CSF at 0.8 and 2 nM,
respectively.15
inhibitors, we first used FieldTemplater (Forge, Cresset)16–26 to
determine the most likely 3D conformation adopted by
BMS-377806,12 BMS-488043,27 BMS-626529,28 and SC11/SC2615
upon binding to the HIV-1 Env target (Fig. 1). This FieldTem-
plater-derived 3D conformation was then used as input into Spark
(Cresset, UK). Spark searches a database of up to 600,000 fragments
to find bioisosteres that exhibit similar shape and electronic prop-
erties as the region of interest when placed in the context of the
final molecule. To maximize the likelihood of identifying interest-
ing potential replacements, we performed bioisosteric searches of
the piperazine groups of BMS-377806, BMS-488043, and
BMS-626529, in addition to the dipyrrolodine group of compounds
SC11/SC26. The results of each search were analyzed and common
structures were identified. From this analysis, four different core
chemotypes were chosen for investigation based upon diversity
and BIF% scores (a factor that indicates how good the replacement
is in the context of the conformation of the entire molecule).
Compounds containing core pyrrolo-pyrazole, azetidine, tetrahy-
dropyridine, azabicyclo-hexane and diazaspiro-decane groups
were then synthesized. First, a common head group to be used in
all of the molecules was synthesized, compound 6, according to
Supplemental Scheme 1. This was subsequently used in the
synthesis of compounds SC12, SC14, SC15, SC27, SC28, and SC45
as outlined in Supplemental Schemes 1–7.
Having successfully demonstrated that scaffold-hopping of the
piperazine moeity can be achieved, in this study we sought to
extend the core chemotypes available for the entry inhibitor class
in the hopes of improving drug-like properties. To accomplish this
we performed computationally directed scaffold-hopping studies,
coupled to synthesis, antiviral potency analysis and computational
3D Quantitative Structure–Activity Relationship (QSAR).
After successful synthesis of each of the five novel-scaffold
derivatives, we then tested them for specificity and potency
against HIV-1. To do this we used the HIV-1 single round infection
assay. In this system, recombinant single-round infectious
envelope-pseudotyped luciferase-reporter HIV-1 viruses are
Due to the lack of structural information on the bioactive
conformation of our inhibitors and the BMS piperazine based
Figure 2. Disparity Matrix showing the pairwise comparisons for the compounds reported using IC50 HIV-1JR-CSF as activity. Red and green boxes correspond to decreases
and increases in activity between the pair, respectively. The darker the shading, the sharper the activity cliff (higher calculated Disparity). The matrix is symmetrical—for
every red box, there is a corresponding green box for the comparison going in the opposite direction.