Influencing Antibody-Mediated Attenuation of Methamphetamine CNS Distribution through Vaccine Linker Design

Active vaccination examining a single hapten engendered with a series of peptidic linkers has resulted in the production of antimethamphetamine antibodies. Given the limited chemical complexity of methamphetamine, the structure of the linker species embedded within the hapten could have a substantial effect on the ultimate efficacy of the resulting vaccines. Herein, we investigate linker effects by generating a series of methamphetamine haptens that harbor a linker with varying amino acid identity, peptide length, and associated carrier protein. Independent changes in each of these parameters were found to result in alterations in both the quantity and quality of the antibodies induced by vaccination. Although it was found that the consequence of the linker design was also dependent on the identity of the carrier protein, we demonstrate overall that the inclusion of a short, structurally simple, amino acid linker benefits the efficacy of a methamphetamine vaccine in limiting brain penetration of the free drug

Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

Human dihydroorotate dehydrogenase (<i>h</i>DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. <i>h</i>DHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of <i>h</i>DHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo­[1,5-<i>a</i>]­pyridine, that has been designed starting from brequinar, one of the most potent <i>h</i>DHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound <b>4</b> also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of <i>h</i>DHODH inhibitors

Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

Human dihydroorotate dehydrogenase (<i>h</i>DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. <i>h</i>DHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of <i>h</i>DHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo­[1,5-<i>a</i>]­pyridine, that has been designed starting from brequinar, one of the most potent <i>h</i>DHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound <b>4</b> also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of <i>h</i>DHODH inhibitors