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Several 2 beta-carboxylic acid ester and amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3 beta-(4'-methylphenyl)- and 3 beta-(4'-chlorophenyl)tropane-2 beta-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3 beta-(4'-chlorophenyl)tropane-2 beta-N-morpholinocarboxamide as well as the 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-N- pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N-dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3 beta-(4'-iodophenyl)-tropane-2 beta-carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.

The adenosine nucleoside analog BCX4430 is a direct-acting antiviral drug under investigation for the treatment of serious and life-threatening infections from highly pathogenic viruses, such as the Ebola virus. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug’s monophosphate nucleotide into the growing RNA chain, causing premature chain termination. BCX4430 is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV and SARS-CoV. In vivo, BCX4430 is active after intramuscular, intraperitoneal, and oral administration in a variety of experimental infections. In nonclinical studies involving lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus, BCX4430 has demonstrated pronounced efficacy. In experiments conducted in several models, both a reduction in the viral load and an improvement in survival were found to be related to the dose of BCX4430. A Phase 1 clinical trial of intramuscular administration of BCX4430 in healthy subjects is currently ongoing.