Orally active, nonpeptide vasopressin V1 antagonists. A novel series of 1-(1-substituted 4-piperidyl)-3,4-dihydro-2(1H)-quinolinones

Abstract

A series of compounds has been synthesized and demonstrated to be antagonists of V1 receptors both in vitro and in vivo. These compounds are structurally related to the 1-(4-piperidyl)-2(1H)-quinolinones, including OPC-21268, an orally bioavailable AVP V1 antagonist with high V1 specificity. It has been found that the introduction of an acetamide group on the terminal alkoxy chain of 41-44 leads to an increase in oral activity. Certain of these compounds may have efficacy in the study of AVP V1 receptors.

Orally Active, Nonpeptide Vasopressin V2 Receptor Antagonists: A Novel Series of 1-[4-(Benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and Related Compounds

“…Benzene-fused hetero rings (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were converted into aniline intermediates 17 by the simple transformations shown in Scheme 2. The starting materials were commercially available or were prepared by published procedures.…”

“…We previously reported a series of 4-(substituted benzoyl)piperidyl 2,3-dihydro quinolinones to be orally effective AVP V 1a receptor antagonists. 8 Although none of the previously reported analogues exhibited any apparent V 2 binding affinity, we have conducted further investigations to find a V 2 antagonist. Starting from the structure of 1, which shows an affinity of 78 µM for V 2 binding, we synthesized a series of more rigid analogues by replacing the piperidyl moiety of 1 with a phenyl ring.…”

“…4 Until recently, all potent AVP receptor antagonists reported have been peptide analogues of AVP [1][2][3][4] and have had poor oral bioavailability, with some exhibiting partial agonistic activity. 6,7 Recently, we 8 and others 9 reported orally effective nonpeptide AVP V 1a antagonists.…”

Characterization of a novel nonpeptide vasopressin V2‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes

“…In the 1990's, we reported orally effective nonpeptide antagonists of AVP receptors, V 1a ‐selective OPC‐21268 (Ogawa et al ., 1993; Yamamura et al ., 1991), V 2 ‐selective OPC‐31260 (Ogawa et al ., 1996; Yamamura et al ., 1992) and OPC‐41061 (Kondo et al ., 1999; Yamamura et al ., 1998). Then several nonpeptide antagonists of AVP receptors, such as V 1a ‐selective SR‐49059 (Serradeil‐Le Gal et al ., 1993), V 2 ‐selective SR‐121463A (Serradeil‐Le Gal et al ., 1996), and VPA‐985 (Albright et al ., 1998), and nonselective YM‐087 (Tahara et al ., 1997) followed.…”

Lysine Vasopressin-Induced Increases in Porcine Myometrial Contractility and Intracellular Ca2+ Concentrations of Myometrial Cells: Involvement of Oxytocin Receptors1

“…It would not be feasible to use these compounds as radioligands for a VP receptor binding study. Recent development of nonpeptide V antagonists may yield highly selective antagonists for these receptors [20] that may prove to be useful for characterization of VP receptors.…”