ABSTRACT
A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
Subject(s)
Indolizines/chemistry , Indolizines/pharmacology , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/metabolism , Animals , Gerbillinae , Humans , Indolizines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.
Subject(s)
Brain/metabolism , Isoindoles/metabolism , Isoindoles/pharmacology , Neurokinin-1 Receptor Antagonists , Administration, Oral , Animals , Aprepitant , CHO Cells , Cricetinae , Cricetulus , Drug Interactions , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Isoindoles/chemical synthesis , Isoindoles/pharmacokinetics , Macaca mulatta , Morpholines/pharmacology , StereoisomerismABSTRACT
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Subject(s)
Neurokinin-1 Receptor Antagonists , Pyrrolidines/pharmacology , Administration, Oral , Animals , Biological Availability , Brain/metabolism , Humans , Macaca mulatta , Pyrrolidines/pharmacokinetics , Species SpecificityABSTRACT
A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.
Subject(s)
Lactams/chemistry , Neurokinin-1 Receptor Antagonists , Cell Line , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK(1) receptor antagonists. Substitution at the 6-exo-position led to high affinity NK(1) antagonists with a prolonged duration of action in vivo. Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel.
Subject(s)
Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Neurokinin-1 Receptor Antagonists , Animals , CHO Cells , Cricetinae , Cyclization , Ether-A-Go-Go Potassium Channels/drug effects , HumansABSTRACT
A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.
Subject(s)
Antiemetics/chemical synthesis , Antiemetics/pharmacology , Lactams/chemistry , Lactams/pharmacology , Tachykinins/antagonists & inhibitors , Amides/chemistry , Animals , Antiemetics/chemistry , Gerbillinae , Humans , Inhibitory Concentration 50 , Lactams/chemical synthesis , Methylation , Molecular Structure , Receptors, Neurokinin-1/metabolism , Structure-Activity Relationship , Tachykinins/metabolismABSTRACT
Extensive screening of compound libraries was undertaken to identify compounds with high affinity for the rat NK(1) receptor based on inhibition of [(125)I]-substance P binding. RP67580, SR140333, NKP-608 and GR205171 were selected as compounds of interest, with cloned rat NK(1) receptor binding K(i) values of 0.15-1.9 nM. Despite their high binding affinity, NKP-608 and GR205171 exhibited only a moderate functional antagonism of substance P-induced inositol-1-phosphate accumulation and acidification rate at 1 microM using cloned or native rat NK(1) receptors in vitro. The ability of the compounds to penetrate the CNS was determined by inhibition of NK(1) agonist-induced behaviours in gerbils and rats. GR205171 and NKP-608 potently inhibited GR73632-induced foot drumming in gerbils (ID(50) 0.04 and 0.2 mg/kg i.v., respectively). In contrast, RP67580 and SR140333 were poorly brain penetrant in gerbils (no inhibition at 10 mg/kg i.v.) and were not examined further in vivo. In rats, only high doses of GR205171 (10 or 30 mg/kg s.c.) inhibited NK(1) agonist-induced sniffing and hypertension, whilst NKP-608 (1 or 10 mg/kg i.p.) was without effect. GR205171 (3-30 mg/kg s.c.) caused only partial inhibition of separation-induced vocalisations in rat pups, a response that is known to be NK(1) receptor mediated in other species. These observations demonstrate the shortcomings of currently available NK(1) receptor antagonists for rat psychopharmacology assays.
Subject(s)
Indoles/pharmacology , Neurokinin-1 Receptor Antagonists , Piperidines/pharmacology , Quinolines/pharmacology , Quinuclidines/pharmacology , Tetrazoles/pharmacology , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Female , Gerbillinae , Humans , Indoles/metabolism , Isoindoles , Male , Piperidines/metabolism , Quinolines/metabolism , Quinuclidines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/metabolism , Tetrazoles/metabolism , Tumor Cells, CulturedABSTRACT
A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.
