title: Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB 223412).
abstract: Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK-3-CHO binding Ki = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding Ki = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 microM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
authors: Department of Medicinal Chemistry, SmithKline Beecham S.p.A., Via Zambeletti, 20021 Baranzate, Milano, Italy.
authors: G A
authors: GA
authors: Giardina
authors: L F
authors: LF
authors: Raveglia
authors: M
authors: M
authors: Grugni
authors: H M
authors: HM
authors: Sarau
authors: C
authors: C
authors: Farina
authors: A D
authors: AD
authors: Medhurst
authors: D
authors: D
authors: Graziani
authors: D B
authors: DB
authors: Schmidt
authors: R
authors: R
authors: Rigolio
authors: M
authors: M
authors: Luttmann
authors: S
authors: S
authors: Cavagnera
authors: J J
authors: JJ
authors: Foley
authors: V
authors: V
authors: Vecchietti
authors: D W
authors: DW
authors: Hay
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects / Q000502:physiology; D051379:Mice; D015877:Miosis / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C054724:senktide; C106716:SB 223412; D013373:Substance P; D002118:Calcium