ABSTRACT
Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
Subject(s)
Central Nervous System/drug effects , Quinolines/chemical synthesis , Receptors, Neurokinin-3/antagonists & inhibitors , Amines/metabolism , Animals , Area Under Curve , Brain/metabolism , Cerebral Cortex/embryology , Gerbillinae , Male , Models, Chemical , Quinolines/metabolism , Quinolines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-hydroxytryptamine(1D) (5-HT(1D)) receptor antagonists have been discovered from elaboration of the series of dual 5-hydroxytryptamine(1)-selective serotonin reuptake inhibitors (5HT(1)-SSRIs) reported previously. This is the first report of highly potent, selective antagonists for the 5-HT(1D) receptor, which represents an extremely useful set of pharmacological tools for further understanding the roles of the 5-HT(1) receptor subtypes.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Binding, Competitive , CHO Cells , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , In Vitro Techniques , Piperazines/chemistry , Piperazines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Serotonin 5-HT1 Receptor Agonists , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.
Subject(s)
Anticonvulsants/chemical synthesis , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Administration, Oral , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/pharmacology , Dose-Response Relationship, Drug , Drug Design , Naphthyridines/pharmacology , Rats , Seizures/drug therapy , Seizures/prevention & control , Structure-Activity Relationship , TetrahydroisoquinolinesABSTRACT
A reusable laparoscopic instrument consisting of a flexible deployment ring and a barrel was fabricated, and an impermeable sac was sutured to the flexible ring before entrapment of the specimen and morcellation. The laparoscopic specimen entrapment device facilitated placement of large renal tumors within a sac for morcellation.
Subject(s)
Kidney Neoplasms/surgery , Laparoscopy/methods , Nephrectomy/instrumentation , Equipment Design , Equipment Reuse , Humans , Nephrectomy/methodsABSTRACT
Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.
