Small-Molecule CD4 Mimics Containing Mono-cyclohexyl Moieties as HIV Entry Inhibitors.

CD4 mimics are small molecules that inhibit the protein-protein interaction between gp120 and CD4, which is a key interaction for the entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono-cyclohexyl-type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR-329, a novel 1-azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti-HIV activity than a previously described lead HAR-171, and modeling results indicated the formation of advantageous interactions by the para-chlorophenyl moiety of YIR-329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono-cyclohexyl-type CD4 mimics with a guanidino group, such as YIR-819 (N(1) -(4-chlorophenyl)-N(2) -(1-(2-(N-(amidino)glycinamide)ethyl)-2-cyclohexylpiperidin-4-yl)oxalamide) and YIR-821 (1-(2-(5-guanidinovaleramide)ethyl derivative of YIR-819), were identified that exhibit approximately fivefold more potent anti-HIV activity than YIR-329. In combination with a neutralizing antibody, their anti-HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR-819 and YIR-821 represent useful lead compounds for the further development of HIV-1 entry inhibitors and could potentially be useful for co-administration with neutralizing antibodies for the treatment of HIV infection and AIDS.

A minimally cytotoxic CD4 mimic as an HIV entry inhibitor.

Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.