History of ACE inhibitors

Current-generation ACE inhibitors (ACEIs) were developed in the late 1970s and early 1980s, and include captopril, enalapril, lisinopril and ramipril. The design of these drugs was the result of guesswork, as neither the sequence nor the structure of ACE was known at that time. Within a few years of their launch, the ACEIs rapidly established themselves as effective agents for the treatment of hypertension and heart failure and quickly became billion-dollar drugs.

Despite this success, up to 20% of patients are unable to tolerate long-term treatment with ACEIs because of side effects, most commonly a persistent dry cough. There are also instances of a more serious adverse effect known as angioedema, which can be life-threatening. These adverse effects are likely related to the fact that treatment with ACEIs not only inhibits the production of angiotensin II but also affects the levels of other active peptides, such as bradykinin.

Company Background

Two of the founders of AngioDesign solved the first three-dimensional structure of ACE at high resolution and this was both a major scientific achievement and a tremendous opportunity for drug discovery. AngioDesign then signed option agreements with the Universities of Cape Town and Bath who owned the intellectual property on the ACE structures. This provided an opportunity for AngioDesign and the universities to develop a solid business plan, identify sources of investment and continue to develop the underlying science. AngioDesign next acquired full ownership of the intellectual property from the universities.

Angiotensin-converting enzyme is a key regulatory enzyme in the cardiovascular system. ACE is a critical component of the renin-angiotensin system (RAS), which controls blood pressure and strongly influences the function of the heart and the kidneys, as well as the walls of blood vessels.

Angiotensin-converting enzyme was shown by AngioDesign’s founders to consist of two similar but non-identical C- and N-domains that each contain an active site with different properties. Detailed knowledge of these differences was essential for the design and synthesis of novel domain-selective inhibitors. Therefore, to improve on the therapeutic efficacy and side effect profile of current-generation ACE inhibitors, it was necessary to have high-resolution structural data for the enzyme. This enabled rational design of domain-selective inhibitors, which will comprise the next-generation ACE inhibitors.

Domain selectivity of ACE

Despite intensive efforts by numerous academic and industry research groups over many years, the ACE crystal structure could not be solved.

Current-generation ACE inhibitors are effective for cardiovascular disease including high blood pressure (BP), heart failure, heart attack and kidney failure but they are hampered by common side effects that limit their use due to an accumulation of bradykinin.
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AngioDesign is developing domain-selective ACE inhibitors, alone and in combination with other inhibitors, which are potentially safer and more effective than existing therapies. Fundamental to this approach is that its:

• C-domain ACE inhibitors decrease BP without increasing bradykinin
• C-domain ACE inhibitors can be modified to develop a new class of C-domain/NEP dual inhibitors that targets new areas, e.g. heart failure
• N-domain ACE inhibitors target new areas, e.g. pulmonary fibrosis.

Pipeline Activities

AngioDesign has concentrated on its core competence in structural biology, structure-guided drug design and lead optimization, and general molecular and cellular expertise in ACE and the renin-angiotensin system (RAS), to build a sustainable pipeline. AngioDesign distinguishes itself from drug discovery companies by focusing on proven drug targets. This greatly de-risks the drug development process and saves time and money. AngioDesign will not invest in genomics- or proteomics-based target identification or validation because of our belief that these efforts remain costly, high-risk, and long-term. Instead, we tend to focus on proven drug targets that have been “neglected” by the pharmaceutical industry because of competition by generic and off-patent drugs.

However, as was shown for inhibitors of cyclooxygenases and histamine receptors, 2nd-generation drugs based on isoform selectivity can become billion-dollar drugs despite an abundance of generic 1st-generation competitors. This is precisely the strategy AngioDesign has pursued with 2nd-generation, domain-selective ACE inhibitors, made possible by the latest available ACE structural information. We will build on our success with 2nd-generation ACE inhibitors to attack other proven drug targets. Structure-guided design techniques will continue to be used to develop proprietary, highly-selective, new-generation inhibitors that will be advanced into early drug development and then licensed out at an appropriate stage.

The principals of AngioDesign have extensive experience in the biotechnology industry, including protein chemistry and drug development, and in financial administration and project management.