Ernest J. McEachern

Intermolecular copper(I) chloride-mediated coupling of alkenyltrialkylstannane functions: A convenient synthesis of conjugated diene systems

Abstract A novel copper(I)-mediated coupling of alkenyltrialkylstannane functions is reported. Thus, treatment of the functionalized stannanes 1–11 with 2.5 equivalents of CuCl in N,N-dimethylformamide (DMF) at room temperature provides good-to-excellent yields of the dienes 12–21 .

Intermolecular homocoupling of alkenyltrimethylstannane functions mediated by CuCl: Preparation of functionalized conjugated diene and tetraene systems

Abstract Copper(I) chloride-mediated oxidative homocouplings of a variety of substrates containing an alkenyltrimethylstannane function are reported. Thus, treatment of each of the stannanes 1–15 with 2.5 equivalents of CuCl in N,N-dimethylformamide (DMF) provides the corresponding dienes or tetraenes 16–32.

Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication

A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.

Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.