Identification and synthesis of major metabolites of Vasopressin V2-receptor agonist WAY-151932, and antagonist, Lixivaptan®

doi:10.1016/j.bmcl.2007.08.053

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 21, 1 November 2007, Pages 5796-5800

https://doi.org/10.1016/j.bmcl.2007.08.053 Get rights and content

Abstract

Small molecule agonists and antagonists of the V₂-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan^®).

Graphical abstract

The synthesis and biological results for metabolites of the above vasopressin agonist 1 and antagonist 2 are presented.

Section snippets

Acknowledgments

We thank Drs. Magid Abou-Gharbia, Ron Magolda, Jay Wrobel, and Jeffrey Pelletier for support and encouragement. We thank Drs. Walter Spinelli and C. H. Park for additional biological data. We also thank Dr. Michael Kagan for valuable scientific suggestions and the assistance of the Department of Analytical Chemistry for analytical data.

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In the fields of allergy and respiration, examples include 2-oxo-3-aminoazepine derivatives which act as dual neurokinin (tachykinin) NK1/NK2 receptor probes for development of options for treatment of asthsma and other airway diseases <07BMCL890> and benzo[1,5]diazepine derivatives as new non-steroidal inhibitors of 17-β-hydroxysteroid dehydrogenase, an enzyme associated with hormone-dependent and neuronal diseases <07JEIMC29>. For the fields of sexual health/urology/gastrointestinal, examples include a benzoxazepinone small molecule antagonist of the parathyroid hormone receptor for identification of small molecule treatments of postmenopausal osteoporosis <07PNAS6846>, a metabolite of vasopression V2-receptor agonist WAY-151932, which has undergone clinical trials for nocturnal enuresis, was found to be biologically equipotent with its clinical lead <07BMCL5796> and 1,4-benzodioxepine derivatives as a novel class of muscarinic receptor antagonists selective for the M3 receptor that display selectivity for the bladder over the salivary gland <07BMCL925>. Tri-and tetra-hydroxyazepanes were shown to be potent glycosidase inhibitors <07JOC4258> while isofagomine tetrahydroxyazepane hybrids were synthesised as β-glucosidase or mannosidase inhibitors <07CC183>.
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^☆: Currently licensed by Wyeth to Cardiokine, Inc., Philadelphia, PA 19102, USA. Tel.: +1 215 399 1200; fax: +1 215 399 1230.

^☆☆: Presented in preliminary form at the ACS 38th National Organic Symposium, Indiana University, Bloomington, IN, USA, June 8–12, 2003.

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Identification and synthesis of major metabolites of Vasopressin V2-receptor agonist WAY-151932, and antagonist, Lixivaptan®☆,☆☆

Abstract

Graphical abstract

Section snippets

Acknowledgments

Hepatology

Hepatology

J. Lab. Clin. Med.

Ann. Rep. Med. Chem

Adv. in Experimental Med. & Biol

Ann. Rev. Physiol

Drugs Future

Identification and synthesis of major metabolites of Vasopressin V₂-receptor agonist WAY-151932, and antagonist, Lixivaptan^®☆,☆☆