Discovery of an orally bioavailable NK1 receptor antagonist, (2S,3S)-(2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine (GR203040), with potent antiemetic activity.
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.
Department of Medicinal Chemistry, Medicines Research Centre, Stevenage, Herts, U.K.
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Ward
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Armour
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Bays
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Evans
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Giblin
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Heron
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Hubbard
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Liang
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Middlemiss
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Mordaunt
D000818:Animals; D000932:Antiemetics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D005260:Female; D005289:Ferrets; D005849:Gerbillinae; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015320:Tachykinins / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014839:Vomiting / Q000188:drug therapy / Q000209:etiology; D014916:Whole-Body Irradiation
D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D015320:Tachykinins; D013777:Tetrazoles; C097591:(2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine