Robert James Weikert

Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors

A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression

Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.

The Florisil® catalyzed [1,3]-sigmatropic shift of allyl phenyl ethers — An entryway into novel mycophenolic acid analogues

Abstract Florisil ® was found to be effective in promoting the [1,3]-sigmatropic shift of mycophenolic acid related allyl phenyl ethers. Several novel mycophenolic acid analogues were thus prepared. Through a crossover experiment using two deuterated analogues of the model system, the reaction was shown to be intramolecular.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors

A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.

Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action

Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.

Results and evaluation of a first‐in‐human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods

The objectives of this first‐in‐human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects.