title: 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.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: E
authors.initials: E
authors.lastname: Ber
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: M
authors.initials: M
authors.lastname: Kurtz
authors.forename: J
authors.initials: J
authors.lastname: Metzger
authors.forename: G
authors.initials: G
authors.lastname: Eiermann
authors.forename: N N
authors.initials: NN
authors.lastname: Tsou
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: R
authors.initials: R
authors.lastname: Hargreaves
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
mesh_terms: D000080:Acetals / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000077608:Aprepitant; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004224:Diterpenes / Q000276:immunology; D004947:Esophagus / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D005260:Female; D005289:Ferrets; D005849:Gerbillinae; D006614:Hindlimb / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D014132:Trachea / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D001743:Urinary Bladder / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D014839:Vomiting / Q000517:prevention & control
chemical_list: D000080:Acetals; D004224:Diterpenes; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant; C024353:resiniferatoxin