ABSTRACT
As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Microsomes/enzymology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , Celecoxib/pharmacology , Cyclooxygenase Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Dogs , Drug Discovery , Humans , Microsomes/drug effects , Models, Molecular , Prostaglandin-E Synthases , Rats , Structure-Activity RelationshipABSTRACT
Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Morpholines/chemical synthesis , Norepinephrine/antagonists & inhibitors , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Biogenic Amines/antagonists & inhibitors , Biogenic Amines/metabolism , Humans , Morpholines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Tin-lithium exchange allows the formation of alpha-amino-organolithium species that undergo anionic cyclization onto allylic ethers to give 3-alkenylpyrrolidines. The methodology has been applied to the synthesis of an advanced intermediate related to the natural product (-)-alpha-kainic acid.
