Firibastat（CAS:648927-86-0)

Firibastat, CAS number 648927-86-0, is a landmark central-targeted antihypertensive API developed by Quantum Genomics, and the world’s first oral prodrug of aminopeptidase A inhibitor capable of penetrating the blood-brain barrier. It fills the long-standing clinical gap that conventional antihypertensives only intervene peripheral renin-angiotensin system (RAS) without regulating central vasopressor pathways, holding exclusive differentiated advantages in salt-sensitive, low-renin and resistant hypertension segments. It is widely adopted in new drug application, generic drug development and cardiovascular pharmacological research. Firibastat appears as white crystalline solid with stable disulfide bond structure, strictly controlled chiral purity and related substances. Limits of heavy metals and residual solvents fully comply with USP and EP pharmacopoeia standards. With favorable water solubility, it supports industrial mass production of oral solid preparations with uniform batch quality, covering full demands from lab-scale research to large-scale formulation manufacturing.

In terms of core pharmacological mechanism, an independent complete RAS system exists inside human brain, and angiotensin III acts as the central core vasopressor peptide with stronger hypertensive activity than angiotensin II. Traditional ACEIs and ARBs only block peripheral angiotensin generation or receptor binding, failing to suppress central conversion of angiotensin II to angiotensin III, which explains poor therapeutic response in salt-sensitive, obese and African hypertensive patients. As a prodrug, oral Firibastat is absorbed through gastrointestinal tract and smoothly crosses blood-brain barrier. Disulfide bonds are cleaved by brain reductases to release two molecules of active metabolite EC33, which selectively binds and inhibits APA enzyme to fundamentally cut off cerebral angiotensin III synthesis. Blocking this pathway reduces central sympathetic tone, improves carotid sinus baroreflex and lowers vasopressin secretion. Three synergistic mechanisms jointly decrease peripheral vascular resistance and blood volume to deliver stable long-term hypotensive effect. Firibastat only targets central APA without interfering peripheral electrolyte transport, so long-term administration avoids hyperkalemia and renal injury, effectively eliminating common adverse risks of ACEIs and mineralocorticoid receptor antagonists.

Clinically, Firibastat is mainly indicated for three types of hypertension poorly controlled by standard therapies: salt-sensitive hypertension, obesity-complicated hypertension and low-renin resistant hypertension, with outstanding efficacy especially for elderly and African patients. Phase 2 NEW HOPE clinical trials verified that monotherapy significantly reduces systolic and diastolic blood pressure, and adding Firibastat to triple antihypertensive regimens further helps patients reach blood pressure targets. Preclinical animal models prove that it inhibits post-myocardial infarction cardiac hypertrophy and myocardial fibrosis, improves left ventricular systolic and diastolic function, delivering dual benefits of hypotension and cardioprotection. It can be freely combined with diuretics, calcium channel blockers and beta blockers with minimal drug-drug interactions, expanding combined therapy options for resistant hypertension, and supporting extended research on adjuvant treatment of chronic heart failure and post-infarction cardiac dysfunction.

Regarding industrial production and clinical safety, Firibastat adopts mature and controllable total synthetic routes with precise purification technology to limit impurities, enabling stable mass production costs and continuous bulk supply for pharmaceutical manufacturers. The standard oral administration regimen is twice daily with excellent overall tolerability. Only mild skin reactions occur in a small number of subjects, without severe liver damage or electrolyte disturbance, presenting a wide safe therapeutic window for long-term medication. As a central antihypertensive API with a brand-new mechanism discovered in the past two decades, Firibastat breaks through the therapeutic bottleneck of existing hypotensive drugs. Facing the huge patient base of resistant hypertension, it possesses irreplaceable market competitiveness in innovative formulation R&D, export API supply and basic cardiovascular medical research, promising stable and broad long-term development prospects across the global pharmaceutical industry.