Hangzhou JINLAN Pharm-Drugs Technology Co., Ltd

1. Core Identifier Common Name: Cobistat English Abbreviation: COBI CAS Number: 1004316-88-4 Chemical Name: (2R,3R,5S)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((1R,2S)-2-(3,5-dimethoxyphenyl)-1-(3-methylbutyl)propyl)oxy)carbonyl)oxy)-1,3-oxothionylpentane-3-carboxylic acid Molecular Formula: C₂₇H₃₆N₂O₉S Molecular Weight: 564.65 g/mol Chemical Structural Characteristics: Belongs to the CYP3A4 specific inhibitors, the molecule contains 3 key structures: oxothionylpentane sugar ring (similar in structure to nucleoside analogs, but without antiviral activity); 3,5- The dimethoxyphenyl side chain (binds to the hydrophobic pocket of the CYP3A4 enzyme active site, which is the core of the inhibitory activity); the carboxylic acid ester group (slowly hydrolyzes in the intestine after oral administration, prolonging the duration of action in vivo); the molecule contains 4 chiral centers (all with specific R/S configurations), only the (2R,3R,5S)/(1R,2S) configuration has CYP3A4 inhibitory activity, and chiral impurities have no synergistic effect and may increase toxicity. 2. Physicochemical Properties (Pharmaceutical Grade API) | Indicator | Typical Parameter | Key Significance (Related to Formulation and Storage) | |---|---|---|---| | Appearance | White to off-white crystalline powder | Oxidation impurities (such as thioether bond oxidation products) can cause a yellowish tint; purity verification requires HPLC. | | Melting Point | 168-172℃ (decomposition point, DSC determination) | Carboxylic acid esters are easily hydrolyzed at high temperatures; formulation processes require temperature control ≤55℃ (e.g., tableting, granulation). | | Solubility | Very slightly soluble in water (<0.1 mg/mL, 25℃, pH 7.0); readily soluble in dimethyl sulfoxide (DMSO, 30 mg/mL) and N,N-dimethylformamide (DMF). | Extremely poor water solubility; micronization technology (D90≤5μm) + hydroxypropyl methylcellulose phthalate (HPMC-P) solid dispersion is required in formulations to improve oral bioavailability (approximately 37% on an empty stomach, increasing to 60% with meals). | | Chiral Purity | Each chiral center has an ee ≥ 99.8%, and diastereomer impurities ≤ 0.2%. Chiral configuration directly determines the binding affinity to CYP3A4, requiring strict stability control by chiral HPLC. Stable for 3 years in sealed, light-protected conditions at room temperature (15-25℃); prone to carboxylic acid ester hydrolysis in humid conditions (RH > 80%), and purity decreases by 1.0% after 24 hours of light exposure (UV 254nm). Requires moisture-proof packaging (e.g., aluminum-plastic blister packs), with a relative humidity ≤ 60% during storage, avoiding prolonged light exposure. pKa 4.3 (carboxylic acid group), 9.1 (pyrimidine ring NH). Protonated in the acidic environment of the stomach (pH 1-3), it is not destroyed by gastric acid after oral administration; taking it with food can delay gastric emptying and increase absorption.