Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

Article

Author: Pannecouque, Christophe ; Shi, Zhongling ; Xie, Minghui ; Zhao, Fabao ; Kang, Dongwei ; Liu, Xinyong ; Zhuo, Zongji ; De Clercq, Erik ; Zhou, Zhenzhen ; Sun, Yanying ; Zhan, Peng

HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared via structural modifications of the leads K-5a2 and 25a. Among them, 15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC₅₀ = 1.75 nmol/L), 3.0-fold (L100I, EC₅₀ = 2.84 nmol/L), 2.4-fold (K103N, EC₅₀ = 1.27 nmol/L), 3.3-fold (Y181C, EC₅₀ = 5.38 nmol/L), 2.9-fold (Y188L, EC₅₀ = 7.96 nmol/L), 2.5-fold (E138K, EC₅₀ = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC₅₀ = 3.76 nmol/L) and 5.3-fold (RES056, EC₅₀ = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound 15a and WT, F227L/V106A, and RES056 RT. Moreover, 15a·HCl carried outstanding pharmacokinetic (t _1/2 = 1.32 h, F = 40.8%) and safety profiles (LD₅₀ > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

01 Dec 2023·Bioorganic & Medicinal Chemistry

In situ click chemistry-based discovery of 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs by exploiting the tolerant region I in binding pocket

Article

Author: Liu, Xinyong ; Pannecouque, Christophe ; Kang, Dongwei ; Feng, Da ; Zhan, Peng ; Zhang, Tao ; Sun, Yanying ; De Clercq, Erik ; Zhou, Zhenzhen

HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC₅₀ = 0.01-0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket.

08 Apr 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

Q1 · MEDICINE

Article

Author: Kang, Dongwei ; Sun, Yanying ; Pannecouque, Christophe ; Liu, Xinyong ; De Clercq, Erik ; Jing, Lanlan ; Feng, Da ; Sun, Lin ; Ruiz, Francesc X. ; Zhan, Peng ; Wang, Zhao ; Zhang, Tao ; Gao, Shenghua ; Arnold, Eddy

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.

100 Deals associated with K-5a2

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	IND Approval	CN	Shandong University	20 Mar 2023
HIV Infections	IND Approval	CN	Shandong Qidu Pharmaceutical Co. Ltd.	20 Mar 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

K-5a2

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation