We
report here the development and optimization of a process synthesis
for the human immunodeficiency virus-1 entry inhibitor BNM-III-170
bis-trifluoroacetate salt (1). The synthesis features
a dynamic-kinetic resolution to establish the initial stereogenicity.
By taking advantage of significant sequence modifications of our first-generation
synthesis, in conjunction with the low solubility of late-stage intermediates,
the overall efficiency of the synthesis has been significantly improved,
now to proceed in an overall yield of 9.64% for the 16 steps, requiring
only a single chromatographic separation.
The human immunodeficiency virus (HIV-1) envelope glycoprotein
(Env) trimer on the virion surface interacts with the host receptors,
CD4 and CCR5/CXCR4, to mediate virus entry into the target cell. CD4-mimetic
compounds (CD4mcs) bind the gp120 Env, block CD4 binding, and inactivate
Env. Previous studies suggested that a C(5)-methylamino methyl moiety
on a lead CD4mc, BNM-III-170, contributed to its antiviral potency.
By replacing the C(5) chain with differentially substituted pyrrolidine,
piperidine, and piperazine ring systems, guided by structural and
computational analyses, we found that the 5-position of BNM-III-170
is remarkably tolerant of a variety of ring sizes and substitutions,
both in regard to antiviral activity and sensitization to humoral
responses. Crystallographic analyses of representative analogues from
the pyrrolidine series revealed the potential for 5-substituents to
hydrogen bond with gp120 Env residue Thr 283. Further optimization
of these interactions holds promise for the development of CD4mcs
with greater potency.
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