A patent review of aldosterone synthase inhibitors (2014-present)

ABSTRACT

Introduction

Aldosterone synthase (AS) is a key enzyme involved in the final three rate-limiting steps of the biosynthesis pathway of aldosterone, and its inhibition has been considered as an effective strategy to treat hypertension, heart failure, and related cardio-metabolic diseases.

Area covered

This review provides an update on the discovery and development of aldosterone synthase inhibitors by means of patents published between January 2014 and March 2021. The molecules are classified by pharmaceutical company with progress that has been made in clinical trials being highlighted.

Expert opinion

Mineralocorticoid receptor antagonists (MRAs) and aldosterone synthase inhibitors (ASI) represent two of the main approaches for the blockade of aldosterone. Clinical success, as well as foreseen side effects of steroidal MRAs, prompted the discovery and development of ASI. Since the observation of decreased cortisol levels in clinical trials for LCI699, subsequent efforts have been largely focused on improving its selectivity over hCYP11B1. Candidates with improved potency and selectivity are under investigation across a wide range of indications. Whether ASI will provide an additional therapeutic advantage over current safe and selective non-steroidal MRAs is highly anticipated.

KEYWORDS:

• Aldosterone synthase
• cortisol synthase
• mineralocorticoid receptor antagonists
• selectivity

Article highlights

• CYP11B2 inhibition prevents the formation of aldosterone and lowers the level in circulating plasma, and thus could be an effective strategy to treat disorders associated with elevated aldosterone levels.

• The safety and feasibility of AS inhibition have been demonstrated clinically by means of several aldosterone synthase inhibitors such as LCI699, LLF269, and RO6836191.

• Selectivity over CYP11B1 is one of the major obstacles for the discovery and development of ASI.

• Ongoing efforts to identify more selective ASI are reviewed by means of patent applications.

Declaration of interest

J Wu, X Ding and X Tan are employees of Roche R&D Center (China) Ltd., Shanghai. 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.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received research grants and honoraria from Bayer SA, Astrazeneca and KBP biosciences. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.