Inosine-5’-monophosphate dehydrogenase (IMPDH) inhibitors: a patent and scientific literature review (2002-2016)

ABSTRACT

Introduction: Inosine-5′-monophosphate dehydrogenase (IMPDH) is an enzyme involved in the de novo biosynthesis of guanine nucleotides. To date human IMPDH inhibitors have been approved for prevention of organ transplant rejection and as anti-viral agents. More recently, the use of IMPDH inhibitors for other indications including cancer and pathogenic microorganisms has been pursued.

Areas covered: IMPDH inhibitors disclosed primarily in the patent and scientific literature from 2002 to the present are discussed. Several interesting chemotypes that have not been pursued by patent protection are also highlighted.

Expert opinion: Progress has been made in the development of IMPDH inhibitors, particularly compounds that are structurally distinct from mycophenolic acid and nucleoside-based inhibitors. However, clinical progression has been hampered primarily by a limited understanding of the enzyme’s role in disease pathophysiology. Finally, most of the IMPDH inhibitors developed over the past fourteen years fall within a relatively narrow set of chemotypes. This provides opportunities for expanding IMPDH inhibitor chemical space to further evaluate this class of molecular targets.

KEYWORDS:

• Anti-bacterial
• anti-protozoan
• anti-viral
• cancer
• IMPDH
• inhibitor
• inosine-5ʹ-monophosphate dehydrogenase
• transplant rejection

Article highlights

• hIMPDH inhibitors have been effective therapeutics for treating transplant rejection and viral infections. However, inhibitors of this molecular target have failed to provide sufficient benefit in the treatment of several other diseases, including cancer, auto-immune diseases and as anti-viral agents.

• The potential use of non-human IMPDH inhibitors has emerged as a strategy to treat infections caused by a subset of protozoans and bacteria, although clinical validation has not been attempted.

• New IMPDH inhibitor chemotypes, not based on mycophenolic acid or nucleosides, have been developed for human and non-human IMPDH isozymes.

• Many of the new inhibitors emanate from urea-based compounds and/or have similar molecular features. This provides potential opportunities to increase the structural diversity of IMPDH inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

One of the authors (GD Cuny) is an inventor on several IMPDH patents and could have a financial interest in the intellectual property. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper has been funded by U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01AI125362, R01AI93459, and R56AI106743] as well as University of Houston and Schrödinger, Inc.