Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

Abstract

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines were designed as non-nucleoside anti-HIV inhibitors targeting reverse transcriptase by a fragment-based replacement strategy with the purpose of improving the druggability. Hopping fiveor six-membered heterocycle groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl gave 23 derivatives. All of these compounds possessed excellent HIV-1 inhibitory activity in the nanomolar range. Among them, 12g with a 4-pyridine group displayed excellent inhibitory activity toward WT and mutant HIV virus possessing significant selectivity. Moreover, this compound exhibited a decent improvement in druggability than etravirine and rilpivirine: (1) The hydrochloric acid salt of 12g exhibited significantly improved water solubility in different pH conditions. (2) 12g did not show apparent CYP enzymatic inhibitory activity or acute toxicity. (3) Excellent oral bioavailability was also revealed (F = 126%, rats) in 12g.Collectively, these novel heteroaromatic-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

“…Suitable solubility was considered to be an essential characteristic of great importance for drug candidates . The salification strategy was confirmed to benefit the solubilities. − We selected compound 6k with the best in vitro activity and evaluated the water solubility of its different salt forms (Table ). The free 6k possessed a solubility of 902.3 μg/mL at pH 2.0, which was about 20-fold higher than that of NXPZ-2 ( S = 47.5 μg/mL).…”

Approved HIV reverse transcriptase inhibitors in the past decade

“…A large number of novel NRTIs and NNRTIs have been reported in the literature 6 , 125 , 126 , 127 , 128 , but only a few candidates are currently evaluated by clinical trials. Most candidates were discontinued because of their limited efficacy, unfavorable side effects, and/or high toxicity.…”

Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

“…The target compounds were mainly synthesized via the Suzuki–Miyaura cross-coupling. The key intermediate 6 and 8 were prepared from 2-mercapto-5-methylpyrimidin-4-ol or 2-mercaptopyrimidin-4-ol according to a four-step protocol which was reported in our previous articles. ,,− For compounds 7a – l , compound 6 reacted with various heterocyclic borates to afford the target compounds in the yield of 58–93%. Similarly, various heterocyclic borates were reacted with 8 to obtain the target compounds 9a – t in the yield of 66–95%.…”

“…Based on the previous structure–activity relationship (SAR) studies, the 4-cyano-biphenyl group was considered as an important pharmacophore for the antiviral activity. , The leading cause for the poor solubility and non-ideal PK profiles is proposed to be the strong hydrophobicity of the biphenyl-DAPYs. Herein, a series of 4-pyridinyl-phenyl-DAPYs were further designed and investigated . Compound 3 was confirmed to possess not only excellent inhibitory activity (EC 50 = 1 nM) but also good solubility ( S = 611 μg/mL, pH = 2.0) .…”