Volume 25, Issue 27
Natural Products
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ChemInform Abstract: 1-(((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido) bicyclo(2.2.1)heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl) piperazine (L-368,899): An Orally Bioavailable, Non-Peptide Oxytocin Antagonist with Potential Utility for Managing Preterm Labor.

P. D. WILLIAMS

P. D. WILLIAMS

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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P. S. ANDERSON

P. S. ANDERSON

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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R. G. BALL

R. G. BALL

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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M. G. BOCK

M. G. BOCK

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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L. CARROLL

L. CARROLL

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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S.-H. L. CHIU

S.-H. L. CHIU

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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B. V. CLINESCHMIDT

B. V. CLINESCHMIDT

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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J. C. CULBERSON

J. C. CULBERSON

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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J. M. ERB

J. M. ERB

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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B. E. EVANS

B. E. EVANS

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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S. L. FITZPATRICK

S. L. FITZPATRICK

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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R. M. FREIDINGER

R. M. FREIDINGER

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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M. J. KAUFMAN

M. J. KAUFMAN

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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G. F. LUNDELL

G. F. LUNDELL

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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J. S. MURPHY

J. S. MURPHY

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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J. M. PAWLUCZYK

J. M. PAWLUCZYK

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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D. S. PERLOW

D. S. PERLOW

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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D. J. PETTIBONE

D. J. PETTIBONE

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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S. M. PITZENBERGER

S. M. PITZENBERGER

Dep. Med. Chem., Merck Res. Lab., West Point, PA 19486, USA

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First published: July 5, 1994

Abstract

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ChemInform Abstract

Modification of the selective, orally active oxytocin (OT) antagonist ( Ia) by introduction of the glutaminylamide moiety as in (Ib) improves the OT receptor affinity. Replacing the carboxamide group with the methylsulfonyl group as in (Ic) results in improved potency for antagonizing OT-induced uterine contractions in vivo by both intravenous and intraduodenal routes of administration. Further enhancement of in vivo potency is achieved by transformation into the tolylpiperazine analogue (IIa). Although measurable increases in OT receptor affinity and in vivo potency are produced by derivatization to (IIb) and (IIc), title compound (IIa) exhibits the best overall profile of OT receptor affinity, potency for inhibition of OT- stimulated contractions of the isolated rat uterus and in situ uterus, aqueous solubility and oral bioavailability.

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