Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel C‑17 Amine Derivatives Based on GSK3640254 as HIV‑1 Maturation Inhibitors with Broad Spectrum Activity

An investigation of the structure–activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on t...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 65; no. 23; pp. 15935 - 15966
Main Authors Hartz, Richard A., Xu, Li, Sit, Sing-Yuen, Chen, Jie, Venables, Brian L., Lin, Zeyu, Zhang, Sharon, Li, Zhufang, Parker, Dawn, Simmons, Tara S., Jenkins, Susan, Hanumegowda, Umesh M., Dicker, Ira, Krystal, Mark, Meanwell, Nicholas A., Regueiro-Ren, Alicia
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 08.12.2022
Amer Chemical Soc
Subjects
Amines - pharmacology
Animals
Chemistry, Medicinal
Dogs
HIV-1
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Rats
Science & Technology
Structure-Activity Relationship
BETULINIC ACID-DERIVATIVES
ANTI-AIDS AGENTS
POTENT
POLYMORPHISMS
BEVIRIMAT
IMMUNODEFICIENCY-VIRUS TYPE-1
GSK3532795
RESISTANCE
ANTIRETROVIRAL THERAPY
REVEALS
Online AccessGet full text

Cover

More Information
Summary:An investigation of the structure–activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01618