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Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro , are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.

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.

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para -substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH 2 F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29 .

GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp 3 -rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3 , which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC 50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In vitro studies suggested that the ammonium salt 2 could be a viable prodrug of the HIV-1 attachment inhibitor 1. Increased systemic exposure of the parent drug 1 following oral administration of the amminium salt 2 when compared to similar studies using solution dosing of the parent compound was observed in the in vivo studies in both rats and dogs. At high doses, the improvement in oral exposure of the parent drug was even more evident, indicating that the increased solubility of the amminium salt 2 can overcome dissolution-limited absorption and demonstrating the potential utility of this compound as a prodrug of 1.

We have recently reported on the discovery of a C-3 benzoic acid ( 1 ) as a suitable replacement for the dimethyl succinate side chain of bevirimat ( 2 ), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C 24 in rat oral PK studies. [ABSTRACT FROM AUTHOR]