Triazole oxytocin antagonists: Identification of an aryloxyazetidine replacement for a biaryl substituent

Alan Brown; T Bruce Brown; Andrew Calabrese; Dave Ellis; Nicholas Puhalo; Michael Ralph; Lesa Watson

doi:10.1016/j.bmcl.2009.11.097

Triazole oxytocin antagonists: Identification of an aryloxyazetidine replacement for a biaryl substituent

Bioorg Med Chem Lett. 2010 Jan 15;20(2):516-20. doi: 10.1016/j.bmcl.2009.11.097. Epub 2009 Nov 23.

Authors

Alan Brown¹, T Bruce Brown, Andrew Calabrese, Dave Ellis, Nicholas Puhalo, Michael Ralph, Lesa Watson

Affiliation

¹ Discovery Chemistry, Pfizer Global Research and Development, Sandwich, United Kingdom. Alan.D.Brown@pfizer.com

PMID: 19963374
DOI: 10.1016/j.bmcl.2009.11.097

Abstract

A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly improved aqueous solubility over related compounds containing a biaryl substituent.

MeSH terms

Administration, Oral
Animals
Antidiuretic Hormone Receptor Antagonists*
Azetidines / chemical synthesis
Azetidines / chemistry*
Azetidines / pharmacokinetics
Dogs
Humans
Microsomes, Liver / metabolism
Oxytocin / analogs & derivatives*
Oxytocin / chemistry
Oxytocin / pharmacokinetics
Rats
Receptors, Vasopressin / metabolism
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacokinetics

Substances

Antidiuretic Hormone Receptor Antagonists
Azetidines
Receptors, Vasopressin
Triazoles
Oxytocin