Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor Antagonist

Abstract

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

“…In line with this view, we show here that the sustained GFT-inhibiting efficacy of aprepitant reflect its in vivo NK 1 R occupancy in the CNS rather than compound levels of at the site of action. Long-lasting effects of aprepitant in GFT have been reported previously (Hale et al, 1998;Duffy et al, 2002), and the excellent correlation between the sustained GFT inhibition and central NK 1 R occupancy in the present study is also consistent with others (Duffy et al, 2002). The present study, however, extends these findings by demonstrating that prominent GFT-inhibiting efficacy of aprepitant persisted even when its CNS levels were below the limit of detection.…”

“…The selective NK 1 R antagonists CP-99994 (McLean et al, 1993) and aprepitant (Hale et al, 1998) and the pan-NK receptor antagonist ZD6021 (Bernstein et al, 2001) were synthesized at AstraZeneca (Mölndal, Sweden).…”

“…Although this approach has been most often used in "organ bath" experiments with intact tissues, it can also be successfully applied in intact cell-based experiments (Vauquelin et al, 2002a). As an illustration of this approach, in vitro assays with NK 1 R-expressing cells pointed at a causal link between the insurmountable behavior of the competitive NK 1 R-selective antagonists SR 140333 and aprepitant and their slow rate of dissociation from the receptor (Emonds-Alt et al, 1993;Hale et al, 1998). That slow dissociation may produce insurmountable inhibition can easily be explained by the fact that the antagonist fails to liberate all the receptor sites during the ensuing challenge with the agonist so that the measured response is suboptimal.…”

Metalloelastase in lungs and alveolar macrophages is modulated by extracellular substance P in mice

“…The gene and protein levels of MMP-12, MMP-9, TIMP-1, and NK1R in AMs were detected in the first and second groups, respectively. The same protocols were repeated in the third and fourth groups, with the exception that CP-99,994 was replaced by aprepitant (10 Ϫ8 M; Merck), another NK1R antagonist (18,33) used in clinic (21). The doses of SP, CP-99,994, and aprepitant were chosen because several investigators have shown that they could sufficiently activate or block NK1R in the cells (28,33,56).…”

The Metabolic Disposition of Aprepitant, a Substance P Receptor Antagonist, in Rats and Dogs

“…More recently, the activation of NK 1 receptors has been linked to the pathoetiology of emesis (Bountra et al, 1993;Beattie et al, 1995;Hale et al, 1998;Rupniak and Kramer, 1999;Diemunsch and Grelot, 2000;Tattersall et al, 2000), pain (Gonzalez et al, 1998;Urban and Fox, 2000), anxiety (Griebel, 1999;Ballard et al, 2001;Cheeta et al, 2001), and depression (Kramer et al, 1998;Maubach et al, 1999). The discovery of nonpeptide, substance P receptor antagonists has led to the development of therapeutic agents for treatment of chemotherapy-induced emesis.…”