864953-39-9

Basic information

• Product Name: BMS 663068 (Tris)
• Synonyms: BMS 663068 (Tris);BMS663068 (Tris);BMS-663068 (Tris);Fostemsavir tromethamine
• CAS NO: 864953-39-9
• Molecular Formula: C29H37N8O11P
• Molecular Weight: 704.624841
• Mol File: 864953-39-9.mol
• Article Data: 7

Chemical Properties

• Appearance: /
• CAS DataBase Reference: BMS 663068 (Tris)(CAS DataBase Reference)
• NIST Chemistry Reference: BMS 663068 (Tris)(864953-39-9)
• EPA Substance Registry System: BMS 663068 (Tris)(864953-39-9)

Safety Data

• Hazardous Substances Data: 864953-39-9(Hazardous Substances Data)

Usage

General Description

BMS 663068, also known as Tris, is a potent and selective inhibitor of HIV-1 integrase, an enzyme required for the replication of the virus. Tris has been studied as a potential treatment for HIV infections, as it has shown the ability to inhibit viral replication and integration into host DNA. In preclinical studies, Tris has demonstrated strong antiviral activity and has the potential to be a key component in combination therapy for HIV. Its mechanism of action involves binding to the integrase enzyme and preventing it from inserting the viral DNA into the host genome, ultimately inhibiting viral replication. BMS 663068 (Tris) represents a promising avenue for the development of new treatments for HIV and has been the focus of ongoing research and clinical trials.

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Relevant articles and documents

Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir

The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies

The development of two enabling routes that led to the production of >1000 kg of BMS-663068 (3) is described. The route identified for the initial 100 kg delivery to support development activities and initial clinical trials involved the conversion of 2-amino-4-picoline to the parent active pharmaceutical ingredient (API), followed by pro-drug installation and deprotection. To eliminate the problematic isolation of the parent API and synthesis of di-t-butyl(chloromethyl)phosphate, a second-generation pro-drug installation route was developed which involved the conversion of a late-stage common intermediate to an N(1)-thioether derivative followed by chloromethylation, displacement with di-t-butylpotassium phosphate, and deprotection. This second strategy resulted in the multikilogram scale preparation of the API in 14 linear steps and ～7% overall yield.

METHODS OF MAKING HIV ATTACHMENT INHIBITOR PRODRUG COMPOUND AND INTERMEDIATES

A method for making the compound of Formula ( I ) is set forth using alkylation, amidation, chlorination and phosphate installation procedures.