1148157-29-2

Usage

Uses

Used in Pharmaceutical Research:
(S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one trifluoroacetate is used as a key intermediate in the synthesis of various pharmaceutical compounds due to its unique structural features and chiral properties. Its ability to form a wide range of derivatives makes it a promising candidate for the development of new drugs and biologically active molecules.
Used in Organic Chemistry and Chemical Synthesis:
In the field of organic chemistry, (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one trifluoroacetate is used as a versatile building block for creating a variety of complex organic compounds. Its specific functional groups and stereochemistry allow for targeted synthesis and modification of molecules, which is crucial in advancing chemical research and development.
Used in Laboratory Settings:
The trifluoroacetate salt form of (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one enhances its stability and solubility, making it easier to handle and work with in laboratory settings. This property is particularly useful for researchers conducting experiments and developing new synthetic methods or drug candidates.

Upstream product

• 1010136-50-1 tert-butyl [(1S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]carbamate 
• 76-05-1 trifluoroacetic acid 
• 87694-53-9 Boc-Phe-OH N,O-dimethyl hydroxamate 
• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 960374-25-8 benzyl (S)-4-methyl-3-oxo-1-phenylpent-4-en-2-ylcarbamate 
• 114744-85-3 [(S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid benzyl ester 
• 1161-13-3 N-Cbz-L-Phe 
• 935888-15-6 benzyl (S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-ylcarbamate 

Downstream Products

• 1083069-64-0 tert-butyl N-[(1S)-2-methoxy-1-{[(1S)-2-methoxy-1-{[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]carbamoyl}ethyl]carbamoyl}ethyl]carbamate 
• 935888-69-0 N-[(2S)-3-methoxy-1-[[(2S)-3-methoxy-1-[[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide 
• 1010136-50-1 tert-butyl [(1S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]carbamate 

Relevant academic research and scientific papers

Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors

Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage prefe

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors

A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.

Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.

GASTRO-RETENTIVE MODIFIED RELEASE DOSAGE FORMS FOR OPROZOMIB AND PROCESS TO MAKE THEREOF

This disclosure features gastro-retentive (GR) modified release pharmaceutical dosage forms (e.g., solid dosage forms, e.g., tablets, e.g., bilayer tablets) that are useful for the oral administration of oprozomib, or a pharmaceutically acceptable salt thereof, to a human or animal subject as well as methods of making and using the dosage form.

Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors

The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition, in particular, the present application includes compounds of Formula I, and compositions and uses thereof.

EPOXYKETONE COMPOUNDS FOR ENZYME INHIBITION

The present disclosure relates to novel compounds and pharmaceutical compositions thereof which are useful as inhibitors of proteasomes. The compounds provided herein have improved proteasome potency and selectivity, and increased aqueous solubility, and

Modified Release Formulations for Oprozomib

This disclosure features modified release pharmaceutical formulations (e.g., extended release pharmaceutical formulations; e.g., solid dosage forms, e.g., tablets) that are useful for the oral administration of oprozomib, or a pharmaceutically acceptable salt thereof, to a human or animal subject as well as methods of making and using the formulations.

METHOD FOR PRODUCING STEREOSELECTIVE EPOXYKETONE COMPOUND

A novel method for producing a stereoselective epoxyketone compound is provided. A method for producing an epoxyketone compound represented by the formula (1), as represented by the following scheme, whereby it is possible to obtain an epoxyketone derivative in good yield and at high selectivity and to provide an industrially useful production method and an intermediate thereof. wherein R1 is a hydrogen atom, a linear, branched or cyclic alkyl group, an aromatic group which may have a substituent, or a heterocyclic group which may have a substituent, and R2 is a protective group for an amino group. R is a hydrogen atom or a C1-10 alkyl group, and R's may be the same or different, provided that at least one R is a C1-10 alkyl group.

CRYSTALLINE TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS

The invention relates to crystalline tripeptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions.

Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047)

Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and Non-Hodgkin's lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (β5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in >proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.