Friday, May 22, 2015

Drugs in Clinical Pipeline: SER100TRISH

SER100TRISH [Ac-RYYRWKKKKKKK-NH2, formerly ZP120] is a novel dodecapeptide with high affinity to the opioid receptor like-1 (ORL1) receptor. The compound acts as a potassium and sodium sparing aquaretic with mild vasodilatory properties and without CNS effects in the expected therapeutic range [1]. Moreover, being a peptide analogue of the endogen peptide nociceptin, SER100TRISH has been shown to have marked aquaretic effects in vivo. However, in addition to this effect SER100TRISH, at least during sodium replete conditions, seems to induce an anti-natriuretic effect by an unknown mechanism.

SER100 was acquired by Serodus from Zealand Pharma A/S in 2010. The development had been stopped since SER100 unexpectedly induced a drop in systolic blood pressure and to a lesser extent in diastolic pressure in patients with acute and chronic heart failure. What Zealand Pharma regarded as a side effect Serodus saw as a potential in patients with treatment resistant isolated systolic hypertension (TR-ISH) [2].

Common Name: SER100TRISH
Synonyms:  SER100TRISH; SER100; ZP120
IUPAC Name: -
CAS Number: -
Mechanism of Action: ORL1 partial agonist
Indication: Treatment Resistant Isolated Systolic Hypertension
Development Stage: Phase II
Company: Serodus

ORL-1 is a G-protein coupled receptor and promotes Ca2+ influx and K+ efflux.  Another property of the receptor is that it occurs presynaptically on a variety of neurons where it inhibits the release of the respective neurotransmitter.  SER100 induces aquaresis by down-regulation of aquaporin-2 in the kidneys and eliciting a mild vasodilatory response without reflex tachycardia (no increase in heart rate).  In animal models the hypotensive effect of SER100 was not affected by other antihypertensives, which predicts that SER100 will be effective as concomitant treatment to products like furosemide, thiazides, beta-blockers, calcium antagonists and ACE inhibitors [2].

Experimental results strongly suggest a direct stimulatory effect of ZP120 on the Epithelial Na+ Channel in the kidney collecting ducts [3].

1. Kapusta, D. R.; et. al. Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity. J Pharmacol Exp Ther 2005, 314(2), 652-660.
3. Petersen, J. S.; et. al. NOP receptor stimulation by ZP120 induces anti-natriuresis through a direct effect on epithelial sodium channel (ENaC) in the renal collecting duct. FASEB J 2008, 22 Meeting Abstract Supplement), 943.5.