Applications of carbonic anhydrases inhibitors in renal and central nervous system diseases

ABSTRACT

Introduction: There are tissues and organs, among which kidneys and the central nervous system (CNS), rich in various isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Their role is to regulate pH, to provide bicarbonate or H⁺ ions for electrolyte secretion and possibly a metabolic one. Considering these two systems, CA inhibitors are clinically used mainly as diuretics and antiepileptics, but novel applications in the management of drug-induced renal injury, sleep apnea, migraine, lowering intracranial pressure, cognitive impairment, neuropathic pain, and cerebral ischemia have emerged.

Areas covered: The various classes of clinically used/investigational CA inhibitors and their applications in the management of renal and CNS – connected diseases is reviewed. A patent and literature review covering the period 2013–2018 is presented.

Expert opinion: Both kidneys and CNS are rich in many CA isoforms (CAIs), present also in high amounts. Their inhibition and activation has pharmacological applications, already exploited for diuretic and antiepileptic drugs for decades. New applications were demonstrated in the last years for the CAIs in the management of idiopathic intracranial hypertension, cerebral ischemia, neuropathic pain, avoiding the disruption of blood-brain barrier, and prevention/treatment of migraine, and for the activators for cognition enhancement and the possible treatment of posttraumatic shock and phobias.

KEYWORDS:

• Carbonic anhydrase inhibitor diuretic
• coumarin
• sulfonamide
• renal injury
• epilepsy
• sleep apnea
• neuropathic pain
• cerebral ischemia
• topiramate
• zonisamide

Article highlights

• Many of the clinically used diuretics (hydrochlorothiazide, hydroflumethiazide, quinethazone, metholazone, chlorthalidone, indapamide, furosemide) but also acetazolamide may be useful for reducing drug-induced nephropathies.

• The renal CAs possess nitrous anhydrase activity and are involved in nitrite resorption and NO metabolism/signaling.

• Many patents of the analyzed period claim sulfonamides based on the SLC-0111 motif

• The antiepileptic CAIs topiramate and zonisamide were claimed to be effective for the treatment of sleep apnea.

• CAIs were demonstrated to be useful in pathologies in great need of new drugs, such as IIH, cerebral ischemia, neuropathic pain, avoiding the disruption of BBB, and prevention/treatment of migraine.

• CAAs have a future in the treatment of posttraumatic shock and phobias, conditions for which few therapeutic options are available.

This box summarizes key points contained in the article.

Declaration of interest

CTS declares being an inventor of many patents claiming carbonic anhydrase inhibitors and their various pharmacological applications. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.