Drug Discovery

Spinifex's AT₂ Receptor Antagonist Technology

Historical Perspective on the Discovery of the AT₂ Receptor

The angiotensin II type 2 (AT₂) receptor was discovered in the late 1980s/early 1990s during the search to find molecules that blocked the binding of angiotensin II (ang II) to what at that stage was thought to be a single type of receptor⁽¹⁾. During this medicinal chemistry process, scientists at companies such as Parke-Davis and DuPont Merck discovered that the tissue they were using for their radio-ligand assays actually contained two main types of receptor that bound ang II, specifically the AT₂ and angiotensin type 1 (AT₁) receptors and that antagonists at only the AT₁ receptor reduced blood pressure. A range of highly selective AT₁ receptor antagonists have now been developed as medicines to treat hypertension (this class of medicine is referred to as ARBs)⁽²⁾. Despite the success of marketed ARBs for hypertension, and while their developers were able to show that selective AT₂ receptor antagonists had no effect on blood pressure, they were unable to identify a human pharmaceutical use for these compounds^(3,4). The initial inventor of Spinifex's technology, Prof. Maree Smith (University of Queensland), has now shown that these AT₂ receptor antagonists relieve symptoms in animal models of neuropathic and inflammatory pain. Since then, Spinifex’s lead product, EMA401, has demonstrated its potential in a Phase 2 clinical trial, showing a significant and clinically meaningful reduction in pain in patients with postherpetic neuralgia, a debilitating condition that can follow shingles.

AT₂ Receptor Drug Discovery Program

In parallel with the clinical development of EMA401 for chronic pain, including neuropathic pain, Spinifex has an active medicinal chemistry program aimed at the discovery and development of further highly selective AT₂ receptor antagonists. These compounds are currently proceeding through hit to lead studies.

⁽¹⁾VanAtten et al, Journal of Medicinal Chemistry, 1993, 36(25), p.3985-3992.
⁽²⁾Wexler et al, Journal of Medicinal Chemistry, 1996, 39(3), p.625-656.
⁽³⁾Steckelings et al, Peptides, 2005, 26, p.1401-1409.
⁽⁴⁾Porrello et al, Frontiers in Bioscience, 2009, 14, p.958-972.