HMG-CoA Reductase inhibitors: an updated review of patents of novel compounds and formulations (2011-2015)

ABSTRACT

Introduction: Statins are remarkably safe and efficient medications that are the mainstay of hypercholesterolemia treatment and have proven to be an invaluable tool to lower the risk of acute cardiovascular events. These compounds are inhibitors of 3-hydroxy-methylglutaryl CoA reductase (HMG-R), the rate-limiting enzyme in cholesterol biosynthesis. In spite of their success, they present undesirable side effects and are now loosing patent protection, which provides a great opportunity for the development of new and improved statins.

Areas covered: This review summarizes the new patents for HMG-R inhibitors for the 2011–2015 period. Combinations of existing statins with other drugs are also addressed, as well as novel applications of existing statins.

Expert opinion: Recent efforts for the discovery of HMG-CoA-R inhibitors has resulted in several new molecules. Most of these are based on commercially available statins, including sterol and terpenoid derivatives. A few peptides have also been patented. However, the origin of the side effects caused by previous statins continues to be, to a large extent, unknown. Although the patents published in the past 5 years are promising, and might result in new drugs, there is still no way to know if they will present reduced toxicity. Only future clinical trials will answer this question.

KEYWORDS:

• Statins
• HMG-R
• sterols
• terpenoids
• new chemical entities
• formulations
• cardiovascular diseases

Article highlights

• Most patented molecules share a significant substructure with existing statins

• New molecular scaffolds include terpenoids, sterols and peptides.

• Novel scaffolds fail to reach low nanomolar activity.

• A significant number of patents describes the use of statins for diseases other than CVD.

• Several patents described the use of adjuvants to potentiate the activity of existing statins for CVD.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

The authors were supported by European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013.UID/MULTI/04378/2013; NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); Fundação para a Ciência e a Tecnologia (FCT) through project EXCL-II/QEQ-COM/0394/2012. AJM Ribeiro acknowledges grant No. SFRH/BPD/94883/2013; E Oliveira acknowledges grant No. SFRH/BD/77625/2011; and D Santos-Martins acknowledges grants No. PTDC/QUI-QUI/102760/2008 and SFRH/DB/84922/2012.