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Department of Chemistry and Chemical Biology at Rensselaer Chemistry and Chemical Biology
Mark P. Wentland
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Mark P. Wentland

Professor, Department of Chemistry and Chemical Biology
Rensselaer Polytechnic Institute

Education:

Ph.D., Organic Chemistry, Rice University, 1970
B.S., Chemistry, Central Connecticut State University, 1966

Career Highlights:

Wentland completed his graduate studies in synthetic organic chemistry in 1970 at Rice University working with the late Professor Robert V. Stevens. He then went to Sterling Winthrop Inc. where he conducted drug discovery research in the medicinal chemistry department for 24 years; his last positions were Sterling Winthrop Fellow and Oncology Discovery Co-Chair. In 1994, he joined the chemistry faculty at Rensselaer. During the period 1971-1994, he was an adjunct professor of chemistry at Rensselaer and taught over 30 graduate-level organic and medicinal chemistry courses.

Research Areas:

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

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). Our publications describing these discoveries as well as a wealth of structure-activity relationship data are catalogued in the PubMed link found below.

Mark P. Wentland research illustration

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. 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

Collaborators: Dr. Jean M. Bidlack and coworkers at the Univ. of Rochester and Alkermes, Inc.

Acknowledgments: This research was supported by the National Institute of Drug Abuse of the National Institutes of Health under award numbers DA12180 and KO5-DA00360. Funding from AMRI, Inc. is also gratefully acknowledged.

Design and Synthesis of MW06-25, a Novel Probe to Study the Pathways of Morphine's Pain-relieving Properties.

Mark P. Wentland research illustration

As part of a large collaborative effort headed by Dr. Lindsay Hough of the Albany Medical College, a report in Nature Neuroscience describes a neuronal P450 epoxygenase that mediates the pain-relieving properties of morphine. A two-tiered approached was used. The first involved a novel transgenic mutant mouse with brain neuron-specific reductions in P450 activity; compared with controls, these mice showed highly attenuated morphine antinociception. The second was a pharmacologic approach where our research group at Rensselaer designed and synthesized MW06-25, a brain P450 arachidonate epoxygenase inhibitor. MW06-25 produced a similar (to the transgenic mouse) block of morphine antinociception in mice.

Collaborators: Dr. Lindsay B. Hough and coworkers at the Center for Neuropharmacology and Neuroscience, Albany Medical College.

Acknowledgments: This research was supported by the National Institute of Drug Abuse of the National Institutes of Health under award number DA03816.

Recent Publications (PubMed Database)

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