The identification of a series of 1,4-benzodiazepin-2-one derived NK1 receptor antagonists is described and a bioactive conformation is proposed. (C) 1997 Elsevier Science Ltd.

The medicinal chemistry strategy is described which led to the identification of GR205171, an orally active non-peptide neurokinin-1 receptor antagonist that is the most potent broad-spectrum antiemetic agent reported to date.

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitutions at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation, This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

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The synthesis and activity of a novel spiro-piperidine non-peptide antagonist (2) of the neurokinin-1 (NK1) receptor is described. Despite having essentially the same solution conformation as CP 99,994 (1) at physiological pH, (2) has reduced affinity for the NK1 receptor.

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.

The synthesis and activity of a novel spiro-piperidine non-peptide antagonist (2) of the neurokinin-1 (NK1) receptor is described. Despite having essentially the same solution conformation as CP 99,994 (1) at physiological pH, (2) has reduced affinity for the NK1 receptor.