ABSTRACT
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
Subject(s)
Cartilage/drug effects , Matrix Metalloproteinase Inhibitors , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Sulfonamides/pharmacology , Animals , Cartilage/metabolism , Cattle , Collagen Type II/metabolism , Crystallography, X-Ray , Inhibitory Concentration 50 , Piperidines/administration & dosage , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Proteoglycans/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman's diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Aldehydes/chemistry , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Butanes/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Imines/chemistry , Stereoisomerism , Sulfonium Compounds/chemistryABSTRACT
A simple and efficient methodology for the synthesis of C(2),N(3)-disubstituted-4 quinazolones from anilines and N-acylanthranilic acids was developed. The new cyclization conditions are much milder than any other reported protocols and resulted in excellent yields (87-98%) without chromatography.
ABSTRACT
DABCO is an extremely active catalyst for the methylation of indoles in conjunction with dimethyl carbonate (DMC). This green chemistry is highly effective and produces N-methylindoles in nearly quantitative yields. The reaction sequence consists of competing alkylation and acylation pathways and involves 1,4-diazabicyclo[2.2.2]octane (DABCO) dually as a nucleophilic catalyst, ultimately resulting in a single product: the N-methylated indole.
ABSTRACT
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is an effective nucleophilic catalyst for carboxylic acid esterification with dimethyl carbonate (DMC). The reaction pathway of this new class of nucleophilic catalysis has been studied. A plausible, multistep mechanism is proposed, which involves an initial N-acylation of DBU with DMC to form a carbamate intermediate. Subsequent O-alkylation of the carboxylate with this intermediate generates the corresponding methyl ester in excellent yield. In the absence of DBU or in the presence of other bases, such as ammonium hydroxide or N-methylmorpholine, the same reaction affords no desired product. This method is particularly valuable for the synthesis of methyl esters that contain acid-sensitive functionality.
