ABSTRACT
Our annulation strategy utilized for the synthesis of 2-azaspiro[3.4]octane is explained. Three successful routes for the synthesis were developed. One of the approaches involved annulation of the cyclopentane ring and the remaining two approaches involved annulation of the four membered ring. All three approaches employ readily available starting materials with conventional chemical transformations and minimal chromatographic purifications to afford the title compound. The merits and limitations of the three approaches are also discussed.
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
Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on ß-keto-γ-lactam 8 to afford ß-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.
Subject(s)
Lactams/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Molecular Structure , Oxidation-Reduction , Selective Serotonin Reuptake Inhibitors/chemistryABSTRACT
The stereospecific synthesis of the PPAR alpha/gamma agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (-30 degrees C), order of addition, and solvent (DMF). The key diastereospecific SN2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described.
Subject(s)
Combinatorial Chemistry Techniques , PPAR alpha/agonists , PPAR gamma/agonists , Propionates/chemical synthesis , Molecular Structure , Stereoisomerism , TemperatureABSTRACT
The synthesis of the peroxime proliferator activated receptor (PPAR) alpha,gamma-agonist (1) was accomplished with high enantio- and diastereoselectivity by employing an asymmetric hydrogenation strategy, of an alpha-alkoxy cinnamic acid derivative, to set the C-2 chiral center. A diastereospecific S(N)2 displacement under mild basic conditions established the C-10 stereochemistry without any detectable racemization of the two epimerizable chiral centers.
Subject(s)
Cinnamates/chemistry , Combinatorial Chemistry Techniques , PPAR alpha/agonists , PPAR gamma/agonists , Propionates/chemical synthesis , Hydrogenation , Molecular Structure , Propionates/chemistry , Propionates/pharmacology , StereoisomerismABSTRACT
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
