113543-30-9

Upstream product

• 646-07-1 4-Methylpentanoic acid 
• 90719-32-7 (S)-4-Benzyl-2-oxazolidinone 
• 38136-29-7 4-methylvaleroyl chloride 
• 2510-33-0 N-benzyl-2-oxazolidinone 
• 79-37-8 oxalyl dichloride 

Downstream Products

• 184844-10-8 (2S,3R)-3-((S)-4-Benzyl-2-oxo-oxazolidine-3-carbonyl)-2-hydroxy-2,5-dimethyl-hexanoic acid methyl ester 
• 184844-11-9 (2R,3R)-3-((S)-4-Benzyl-2-oxo-oxazolidine-3-carbonyl)-2-hydroxy-2,5-dimethyl-hexanoic acid methyl ester 
• 191664-13-8 N-[(R)-2-((S)-4-Benzyl-2-oxo-oxazolidine-3-carbonyl)-4-methyl-pentyl]-benzamide 
• 144287-83-2 (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-methylhexanoate 
• 112245-04-2 (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-methylpentanoic acid 
• 210345-89-4 (2R)-([amino]methyl)-4-methylpentanoic acid 
• 191664-17-2 (R)-2-[((R)-3-tert-Butoxycarbonylamino-2-methyl-propionylamino)-methyl]-4-methyl-pentanoic acid benzyl ester 
• 191664-18-3 (R)-2-({(R)-3-[(R)-2-(tert-Butoxycarbonylamino-methyl)-3-methyl-butyrylamino]-2-methyl-propionylamino}-methyl)-4-methyl-pentanoic acid benzyl ester 
• 191664-19-4 C₄₆H₇₈N₆O₉ 
• 207686-09-7 (2S,3R)-2-Hydroxy-3-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-2,5-dimethyl-hexanoic acid 
• 207686-13-3 (2R,3R)-2-Hydroxy-3-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-2,5-dimethyl-hexanoic acid 
• 207686-02-0 (2S,3R)-2-Hydroxy-3-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-2,5-dimethyl-hexanoic acid methyl ester 
• 207686-06-4 (2R,3R)-2-Hydroxy-3-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-2,5-dimethyl-hexanoic acid methyl ester 

Relevant academic research and scientific papers

Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity

Matrix metalloproteinases (MMPs) are zinc endopeptidases that play roles in numerous pathophysiological processes and therefore are promising drug targets. However, the large size of this family and a lack of highly selective compounds that can be used for imaging or inhibition of specific MMPs members has limited efforts to better define their biological function. Here we describe a protein engineering strategy coupled with small-molecule probe design to selectively target individual members of the MMP family. Specifically, we introduce a cysteine residue near the active-site of a selected protease that does not alter its overall activity or function but allows direct covalent modification by a small-molecule probe containing a reactive electrophile. This specific engineered interaction between the probe and the target protease provides a means to both image and inhibit the modified protease with absolute specificity. Here we demonstrate the feasibility of the approach for two distinct MMP proteases, MMP-12 and MT1-MMP (or MMP-14).

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.

Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI)

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.

N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.

CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF

The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.

Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis

Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against

CYCLIC AMINE COMPOUND

The present invention provides an excellent antihypertensive medicament. The medicament of the present invention comprises a compound having the general formula (I) and the like: [wherein R1: H, substitutable alkyl, substitutable alkenyl, substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; R2: H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R3, R4; H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R5, R6: H, substitutable alkyl, substitutable cycloalkyl, substitutable alkoxy or the like; R7, R8: H, substitutable alkyl, substitutable cycloalkyl or the like; X: the formula (II) or the like; A: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; Y: a single bond, substitutable alkylene, substitutable alkenylene, -(CH2)a-X1-(CH2)b- (X1: the formula -NH-, -O- or the like; a, b: 0-5) or the like; B: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like].

DUAL-ACTING ANTIHYPERTENSIVE AGENTS

The invention relates to compounds having the formula: (I) wherein: Ar, r, R3, Z, X, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Dual-acting antihypertensive agents

The invention is directed to compounds having the formula: wherein: Ar, r, Y, Z, Q, W, X, and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

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.