Jean M. Bidlack, Ph.D.

Discovery of Samidorphan, a medication currently in multiple Phase 2 and Phase 3 clinical trials:

In collaboration with Dr. Mark P. Wentland at Rensselaer Polytechnic Institute, the main goal of our research is to design, synthesize and characterize oral, long-acting modulators of opioid G protein-coupled receptors (GPCRs) as medications to treat cocaine abuse and other central nervous system disorders in humans. A common structural feature of the large majority of opioids is a phenolic-OH group (see prototypic opioid structure below) that plays a crucial role in molecular recognition via H-bonding to a histidine residue of an opioid GPCR. For many opioids, however, this OH group is responsible for poor oral bioavailability and/or short half-life via O-glucuronidation. In 2001, we published the first report that a carboxamide group (CONH2) was an effective replacement for this prototypic phenolic-OH group of opioids. In addition to high affinity binding to opioid GPCRs, certain carboxamido-substituted opioids have much improved pharmacokinetic properties (relative to their phenolic-OH counterparts) as a consequence of high metabolic stability.

Since 2001, our research group has focused on capitalizing on this discovery to achieve our main goal. Our first-generation opioid modulator in this series was 8-carboxamidocyclazocine (8-CAC) and a next generation agent is samidorphan (formerly referred to as ALKS 33). 8-CAC produced analgesia in mice for 16 hours in comparison to morphine which produces analgesia for less than 2 hours. Our publications describing these discoveries as well as a wealth of structure-activity relationship data are catalogued in the PubMed link found below.

In September 2006, Rensselaer signed a license agreement granting Alkermes Inc. - a biotechnology company now based in Ireland - exclusive rights to a library of opioid compounds discovered by our team. The Bidlack lab continues to work with Alkermes to discover new opioids that may be pharmacotherapeutics. Alkermes recently announced the initiation of multiple phase 3 clinical studies of ALKS 5461 (samidorphan in combination with buprenorphine) for treatment of patients with major depressive disorder. The U.S. Food and Drug Administration (FDA) has granted Fast Track status for ALKS 5461. Alkermes also announced the initiation of multiple phase 2 clinical studies of ALKS 3831, a novel oral atypical antipsychotic drug candidate designed to be a broad spectrum treatment for schizophrenia. ALKS 3831 is composed of samidorphan in combination with the established antipsychotic drug, olanzapine. See the following press releases from Alkermes for details:

Alkermes Announces Initiation of FORWARD-3 and FORWARD-4 Efficacy Studies in Pivotal Program for ALKS 5461 for Treatment of Major Depressive Disorder

Alkermes Announces Initiation of ALKS 5461 Pivotal Clinical Program for Treatment of Major Depressive Disorder

Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder

Alkermes Announces Initiation of Second Phase 2 Clinical Study of ALKS 3831, a Novel Broad-Spectrum Oral Antipsychotic

Alkermes Announces Initiation of Phase 2 Clinical Study of ALKS 3831, Designed to Be a Broad Spectrum Oral Antipsychotic for the Treatment of Schizophrenia