Abstract |
The antiemetic, pharmacokinetic, and metabolic profile of CP-99,994, a potent NK1 receptor antagonist, has been carefully evaluated. As a result we began a medicinal chemistry program which initially identified a 3-furanyl analogue (6) with improved antiemetic potency and a methyl sulfone (5) with enhanced metabolic stability and oral bioavailability. The improved pharmacokinetic profile of methyl sulfone (5) was associated with its low lipophilicity, and a therefore a number of heterocyclic analogues with reduced log D were synthesized. Out of this program emerged 19 ( GR203040), a tetrazolyl-substituted analogue. Tetrazole 19 inhibits radiation-induced emesis in the ferret with high potency when administered both subcutaneously and orally, has a long duration of action, and has high oral bioavailability in the dog. Tetrazole 19 is currently undergoing evaluation as a novel approach for the control of emesis associated with, for example, cancer chemotherapy.
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Authors | P Ward, D R Armour, D E Bays, B Evans, G M Giblin, N Heron, T Hubbard, K Liang, D Middlemiss, J Mordaunt |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 38
Issue 26
Pg. 4985-92
(Dec 22 1995)
ISSN: 0022-2623 [Print] United States |
PMID | 8544174
(Publication Type: Journal Article)
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Chemical References |
- Antiemetics
- Neurokinin-1 Receptor Antagonists
- Piperidines
- Tachykinins
- Tetrazoles
- (2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine
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Topics |
- Animals
- Antiemetics
(chemistry, pharmacokinetics, pharmacology)
- Biological Availability
- CHO Cells
- Cell Membrane
(metabolism)
- Cricetinae
- Dogs
- Female
- Ferrets
- Gerbillinae
- Magnetic Resonance Spectroscopy
- Male
- Neurokinin-1 Receptor Antagonists
- Piperidines
(chemistry, pharmacokinetics, pharmacology)
- Tachykinins
(metabolism)
- Tetrazoles
(chemistry, pharmacokinetics, pharmacology)
- Vomiting
(drug therapy, etiology)
- Whole-Body Irradiation
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