title: Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.
abstract: In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.
authors.affiliation: GlaxoSmithKline, Department of Pulmonary Biology, King of Prussia, Pennsylvania 19406, USA. douglas_w_hay@sbphrd.com
authors.forename: Douglas W P
authors.initials: DW
authors.lastname: Hay
authors.forename: Giuseppe A M
authors.initials: GA
authors.lastname: Giardina
authors.forename: Don E
authors.initials: DE
authors.lastname: Griswold
authors.forename: David C
authors.initials: DC
authors.lastname: Underwood
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Kotzer
authors.forename: Brian
authors.initials: B
authors.lastname: Bush
authors.forename: William
authors.initials: W
authors.lastname: Potts
authors.forename: Punam
authors.initials: P
authors.lastname: Sandhu
authors.forename: Dave
authors.initials: D
authors.lastname: Lundberg
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Dulcie B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: Lenox D
authors.initials: LD
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Kilian
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Legos
authors.forename: Frank C
authors.initials: FC
authors.lastname: Barone
authors.forename: Mark A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: Mario
authors.initials: M
authors.lastname: Grugni
authors.forename: Luca F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sarau
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D019343:Citric Acid; D003001:Cloning, Molecular; D003371:Cough / Q000139:chemically induced / Q000517:prevention & control*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015288:Neurokinin A / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000085:Acetates; D000996:Antitussive Agents; C444647:N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide; D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D011994:Recombinant Proteins; C054724:senktide; D019343:Citric Acid; D013373:Substance P; D015288:Neurokinin A; D002118:Calcium