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Vol. 300, Issue 1, 314-323, January 2002
GlaxoSmithKline, Departments of Pulmonary Biology (H.M.S., D.E.G.,
J.J.F., D.B.S., L.D.M., M.A.L., D.W.P.H., D.K., D.C.U., C.J.K.), Drug
Metabolism and Pharmacokinetics (B.B., W.P., P.S., D.L.), and
Cardiovascular Biology (J.J.L., R.G.W., F.C.B.), King of Prussia,
Pennsylvania; and Department of Medicinal Chemistry (G.A.M.G., M.G.,
L.F.R.), Milan, Italy
In this report the in vitro and in vivo pharmacological and
pharmacokinetic profile of
(
)-(S)-N-(
-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 125I-[MePhe7]-neurokinin B
(NKB) binding to membranes of Chinese hamster ovary (CHO) cells
expressing the hNK-3R (CHO-hNK-3R) with a
Ki = 2.2 nM and antagonized
competitively NKB-induced Ca2+ mobilization in human
embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R)
with a Kb = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated
iris sphincter (pA2 = 8.1) and guinea pig ileal
circular smooth muscles (pA2 = 8.3). SB 235375 was
selective for the hNK-3R compared with hNK-1
(Ki > 100,000 nM) and hNK-2 receptors
(Ki = 209 nM), and was without effect,
at 1 µM, 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 (ED50 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.
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