191406-75-4

Upstream product

• 100-39-0 benzyl bromide 
• 148415-75-2 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid 
• 184489-29-0 (2R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid 
• 191406-74-3 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutylhex-5-enoic acid benzyl ester 

Downstream Products

• 191407-51-9 1-benzyl 4-tert-butyl (2R,3S)-2-isobutyl-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate 
• 191409-14-0 (6S,7R,10S)-7-Isobutyl-8-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1⁽¹⁵⁾,12⁽¹⁶⁾,13-triene-6,10-dicarboxylic acid 6-(benzyloxy-amide) 10-{[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethyl]-amide} 

Relevant academic research and scientific papers

Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.

NOVEL MATRIX METALLOPROTEINASE INHIBITORS AND IMAGING AGENTS, AND METHODS USING SAME

The present invention provides certain compounds, Formula (I), or salts or solvates thereof, which can be used as matrix metalloproteinase-targeted inhibitors or imaging agents.

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor α release in vitro and in vivo

To search for TNF-α (tumor necrosis factor α) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2′ residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1 P1-P2′ linkers. With an N-methylamide at P3′, the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-α release from LPS-stimulated human whole blood. Further elaboration in the P3′-P4′ area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of ≤0.2 μM in whole blood assay (WBA). Although the P3′ area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3′ was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3′, an N-methylamide at P4′ provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 μM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4′ afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBAIC50 = 0.067 μM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with Ki values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

Macrocyclic compounds as metalloprotease inhibitors

This invention relates to macrocyclic molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor. The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases.

Macrocyclic hydroxamate inhibitors of matrix metalloproteinases and TNF- α production

Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and turnout necrosis factor-α (TNF-α) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A