Design and optimization of potent, selective antagonists of Oxytocin

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 15, 2008, Pages 4278-4281

  Brown, Alan ^a   Brown, Lindsay ^a   Ellis, Dave ^a   Puhalo, Nicholas ^a   Smith, Chris R ^a   Wallace, Olga ^a   Watson, Lesa ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Antagonist; Oxytocin; Triazole

Indexed keywords

OXIME; OXYTOCIN ANTAGONIST; PIPERAZINEDIONE; PIPERIDINAMIDE; SULFONAMIDE; TRIAZOLE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SOLUBILITY; EXPERIMENTAL RAT; HIGH THROUGHPUT SCREENING; IN VIVO STUDY; NONHUMAN; PHARMACOPHORE; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; COMBINATORIAL CHEMISTRY TECHNIQUES; MOLECULAR STRUCTURE; OXYTOCICS; OXYTOCIN; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

RATTUS;

EID: 47749133751     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.06.098     Document Type: Article

References (19)

1. Gullam J.E., Chatterjee J., and Thornton S. Drug Discovery Today: Ther. Strateg. 2 (2005) 47-52
2. Tiwari A., Nanda K., and Chugh A. Expert Opin. Investig. Drugs 14 (2005) 1359-1372
3. See, for example, WO 2005028452 and the references therein.
4. Williams P.D., Anderson P.S., Ball R.G., Bock M.G., Carroll L., Lee Chiu S.-H., Clineschmidt B.V., Chris Culberson J., Erb J.M., et al. J. Med. Chem. 37 (1994) 565-571
5. Williams P.D., Clineschmidt B.V., Erb J.M., Freidinger R.M., Guidotti M.T., Lis E.V., Pawluczyk J.M., Pettibone D.J., Reiss D.R., et al. J. Med. Chem. 38 (1995) 4634-4636
6. Borthwick A.D., Davies D.E., Exall A.M., Hatley R.J.D., Hughes J.A., Irving W.R., Livermore D.G., Sollis S.L., Nerozzi F., Valko K.L., Allen M.J., Perren M., Shabbir S.S., Woollard P.M., and Price M.A. J. Med. Chem. 49 (2006) 4159-4170
7. Borthwick A.D., Davies D.E., Exall A.M., Livermore D.G., Sollis S.L., Nerozzi F., Allen M.J., Perren M., Shabbir S.S., Woollard P.M., and Wyatt P.G. J. Med. Chem. 48 (2005) 6956-6969
8. See WO2002102799.
9. Hopkins A.L., Groom C.R., and Alex A. Drug Discovery Today 9 (2004) 430-431
10. All data reported herein represents functional antagonism, as measured against the corresponding cloned human receptor in a cell based β lactamase reporter assay, using technology licensed from Rhoto Pharmaceuticals.
11. Kakefuda A., Suzuki T., Tobe T., Tahara A., Sakamoto S., and Tsukamoto S.-i. Bioorg. Med. Chem. 10 (2002) 1905
12. See for example. Leeson P.D., and Springthorpe B. Nat. Rev. Drug Disc. 6 (2007) 881-890 and the references therein
13. 1B activity was detected (at 10 μM) for any of the compounds screened in the series disclosed in this letter.
14. Subsequent analysis across this series suggested that there was indeed a greater probability of achieving improved in vitro metabolic stability at lower clog P.
15. Aqueous solubilities measured for compounds 13 and 17 were 6 μg/ml at pH 7.4 and 24 μg/ml at pH 7.2, respectively; solubilities measured on fully crystalline material.
16. Rat PK parameters were as follows. (a) Compound 13: oral pharmacokinetics (dose: 0.5 mg/kg of a crystalline suspension)-Cl 50 ml/min/kg; T1/2 1 h; F 24%. Iv pharmacokinetics (1 mg/kg bolus dose)-Cl 48 ml/min/kg. (b) Compound 17: oral pharmacokinetics (dose 2 mg/kg of a crystalline suspension) Cl 28 ml/min/kg; T1/2 0.7 h; F 30%. Iv pharmacokinetics (2 mg/kg, bolus dose)-Cl 28 ml/min/kg.
17. Representative examples of (off target) pharmacology targets against which 13 and 17 were profiled: Angiotensin Converting Enzyme; human Cyclooxygenase 2 enzyme; human 5-HT1A receptor; human Endothelin A and B receptors; human Cannabinoid 1 and 2 receptors; hERG Potassium channel.
18. See. Bedford R.B., and Cazin C.S.J. Chem. Commun. (2001) 1540-1541 Suzuki catalyst 3 from this paper was utilised in this coupling. More generally, this catalyst was successfully utilised in a wide range of related Suzuki couplings in this series
19. +].