Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent review

ABSTRACT

Introduction: Prolylcarboxypeptidase (PrCP) is a serine protease that produces or degrades signaling proteins in several important pathways including the renin-angiotensin system (RAS), kallikrein-kinin system (KKS) and pro-opiomelanocortin (POMC) system. PrCP has the potential to be a therapeutic target for cardiovascular, inflammatory and metabolic diseases. Numerous classes of PrCP inhibitors have been developed by rational drug design and from high-throughput screening hits. These inhibitors have been tested in mouse models to assess their potential as new therapeutics.

Areas Covered: This review covers the relevant studies that support PrCP as a target for drug discovery. All the significant patent applications and primary literature concerning the development of PrCP inhibitors are discussed.

Expert Opinion: The pathways where PrCP is known to operate are complex and many aspects remain to be characterized. Many potent inhibitors of PrCP have been tested in vivo. The variable results obtained from in vivo studies with PrCP inhibitors suggest that additional understanding of the biochemistry and the required therapeutic inhibitor levels is necessary. Additional fundamental research into the signaling pathways is likely required before the true therapeutic potential of PrCP inhibition will be realized.

KEYWORDS:

• Prolylcarboxypeptidase
• lysosomal Pro-X carboxypeptidase
• angiotensinase C
• diet-induced obesity
• hypertension
• pro-opiomelanocortin system
• POMC
• kallikrein-kinin system
• KKS
• renin-angiotensin system
• RAS
• melanocyte-stimulating hormone
• alpha-MSH
• enzyme inhibitor
• high-throughput screening
• rational drug design

Article highlights

• PrCP is involved in producing or degrading signaling proteins in several important pathways and is a potential therapeutic target for cardiovascular, inflammatory and metabolic diseases.

• Eight patent applications that disclose small molecule inhibitors of PrCP have been published. Merck & Co., Inc., Kenilworth, NJ, USA has been the only company known to be active in the area.

• The data for five additional classes of inhibitors have been published in the primary literature in addition to the published patent applications.

• Several in vivo studies in preclinical species evaluating various inhibitors for appetite suppression, body mass reduction and protection from diet-induced obesity have had variable outcomes.

This box summarizes key points contained in the article.

Declaration of interest

TH Graham the author is an employee and common stock shareholder of Merck & Co Inc. research laboratories. 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 was funded by Merck & Co Inc. research laboratories.