OPC‐21268: An Orally Effective, Nonpeptide Vasopressin V₁ Antagonist

Abstract

Arginine vasopressin (AVP) is among the strongest vasoconstrictors (mediated by V, receptors) and is also an osmotic and body fluid regulator through renal water reabsorption (mediated by V, receptors). The classification of AVP receptors was originally based on intracellular mechanisms: CAMP-independent (V,) and CAMP-dependent (V,) pathways. The intracellular mechanisms of action of V, receptor was explained by the activation of phospholipase C and the subsequent mobilization of intracellular Ca2+ and activation of protein kinase C (10). The angiotensin I1 (ANG 11) type 1 receptor (vascular type) has a common intracellular signal transduction pathway. In patients with congestive heart failure (CHF) (13) and essential hypertension (HT) (3), plasma concentrations of AVP and ANG II are elevated although vascular tone is usually inadequately high in these conditions. Inhibition of ANG I1 action by angiotensin converting enzyme (ACE) inhibitors in HT and CHF have been successful (15); ACE inhibitors improve the cardiac performance acutely via vasodilation and inhibition of water retention and also the long-term prognosis. Several studies suggest that direct cardiac effects of ANG I1 also play an important role in the long-term prognosis of CHF. An intravenous V, blocker decreases the blood pressure in patients with HT as do intravenous ANG I1 blockers. Cardiac muscle also has V, receptors (1).These reports suggest that a V, antagonist may have a similar beneficial effect in the treatment of HT and CHF as ACE inhibitors do. Many kinds of AVP antagonists have been developed for therapeutic use, but all were peptide analogues and do not have oral bioavailability (8). Recently, an orally active, nonpeptide form of V, antagonist, OPC-21268, has been selected from thousands of synthetic compounds (19). CHEMISTRYOPC-21268, i.e., 1-{ 1-[4-(3-acetylaminopropoxy)benzoyl]-4-pipe~dyl}-3,4-dihydro-2(1H)-quinolinone (Fig. l), was synthesized by Yamamura and colleagues of Otsuka

Small molecule ligands for oxytocin and vasopressin receptors

“…31 In preliminary studies, it was reported that orally administered OPC-21268 produced some blockade of AVP-induced vasoconstriction in human forearm vasculature 31a and transiently reduced blood pressure in a patient with diabetic renal failure. 32 OPC-21268, which has recently been reviewed, 33,26 will be a useful tool for studies of AVP physiology and may lead to orally active therapeutic agents.…”

“…26 This nonpeptidyl dihydroquinolinone structure, termed OPC-21268 (Fig. 3), was developed by optimization of a lead molecule found through random screening of several thousand compounds.…”