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Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI., Methods: Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort., Conclusion: The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ethan Weinberg.•Mallinckodt Pharmaceuticals: study funding, DSMB/Advisory board participation•BioVie: consulting•PharmaIN: consulting•Institute for Medical and Nursing Education: lectures/presentations Stevan A. Gonzalez.•Mallinckrodt Pharmaceuticals: advisory board, consulting, Speakers bureau•Salix Pharmaceuticals: consulting, Speakers bureau•AbbVie Pharmaceuticals: Speakers bureau R. Todd Frederick.•Mallinckrodt Pharmaceuticals: consultant Raymond A. Rubin.•Mallinckrodt Pharmaceuticals: clinical trial funding, Speakers bureau William Tobin.•Services contract with UPenn to monitor study data Khurram Jamil.•Mallinckrodt Pharmaceuticals: employee, patents, stock Zachary Fricker.•Mallinckrodt Pharmaceuticals: payments to institution and travel reimbursements K. Rajender Reddy.•Grants/contracts: BMS, Intercept, Mallinckrodt, BioVie, Sequana, Grifols, Exact Sciences, HCC-TARGET, NASH-TARGET, Merck•Royalties/licenses: UpToDate•Consulting: Spark Therapeutics, Novo Nordisk, Mallinckrodt, Genfit, BioVie•DSMB/Advisory Board participation: Novartix, Astra Zeneca•Associate Editor Gastroenterology No disclosures:•Suditi Rahematpura, Manhal J. Izzy, Douglass A. Simonetto, Jade Ikahihifo-Bender, Maggie Harte, Grace Kim-Lee, Sherry Witkiewicz, (© 2023 The Authors.)

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.

The widespread misuse of opioids and opioid use disorder (OUD) together constitute a major public health crisis in the United States. The greatest challenge for successfully treating OUD is preventing relapse. Unfortunately, there are few FDA-approved medications to treat OUD and, while effective, these pharmacotherapies are limited by high relapse rates. Thus, there is a critical need for conceptually new approaches to developing novel medications to treat OUD. Here, we review an emerging preclinical literature that suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists could be re-purposed for treating OUD. Potential limitations of this approach are also discussed along with an alternative strategy that involves simultaneously targeting and activating GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) in the brain using a novel monomeric dual agonist peptide. Recent studies indicate that this combinatorial pharmacotherapy approach attenuates voluntary fentanyl taking and seeking in rats without producing adverse effects associated with GLP-1R agonist monotherapy alone. While future studies are required to comprehensively determine the behavioral effects of GLP-1R agonists and dual agonists of GLP-1Rs and Y2Rs in rodent models of OUD, these provocative preclinical findings highlight a potential new GLP-1R-based approach to preventing relapse in humans with OUD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There has been a dramatic increase in illicit fentanyl use in the United States over the last decade. In 2018, more than 31,000 overdose deaths involved fentanyl or fentanyl analogs, highlighting an urgent need to identify effective treatments for fentanyl use disorder. An emerging literature shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the reinforcing efficacy of drugs of abuse. However, the effects of GLP-1R agonists on fentanyl-mediated behaviors are unknown. The first goal of this study was to determine if the GLP-1R agonist exendin-4 reduced fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, an animal model of relapse, in rats. We found that systemic exendin-4 attenuated fentanyl taking and seeking at doses that also produced malaise-like effects in rats. To overcome these adverse effects and enhance the clinical potential of GLP-1R agonists, we recently developed a novel dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs), GEP44, that does not produce nausea-like behavior in drug-naïve rats or emesis in drug-naïve shrews. The second goal of this study was to determine if GEP44 reduced fentanyl self-administration and reinstatement with fewer adverse effects compared to exendin-4 alone. In contrast to exendin-4, GEP44 attenuated opioid taking and seeking at a dose that did not suppress food intake or produce adverse malaise-like effects in fentanyl-experienced rats. Taken together, these findings indicate a novel role for GLP-1Rs and Y2Rs in fentanyl reinforcement and highlight a potential new therapeutic approach to treating opioid use disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC 50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.

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.)

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

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.)

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 C24 in rat oral PK studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein., (Copyright © 2015 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.

A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The UGT1A1*28 polymorphism is known to correlate with altered clearance of bilirubin (Gilbert syndrome) and drugs such as 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11). Although this polymorphism is clinically relevant and leads to significant drug-related toxicity of CPT-11, in vitro tools to allow prediction of how it will affect the clearance of new chemical entities have not been completely developed. To allow a more complete assessment of whether new chemical entities will be affected by the UGT1A1*28 polymorphism, a panel of microsomes was prepared from 15 donor livers genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28 (five donors per genotype). The microsomes were phenotyped by measuring activities of a panel of substrates, both those reported to be conjugated specifically by UGT1A1 or by other UDP glucuronosyltransferase enzymes. Bilirubin, estradiol (3-OH), ethinyl estradiol (3-OH), and 7-ethyl-10-hydroxycamptothecin (SN-38) were found to show significantly lower rates of metabolism in the UGT1A1*28/*28 microsomes with no change in K(m) values. In addition, microsomes genotyped as UGT1A1*1/*28 showed intermediate rates of metabolism. Acetaminophen, 3'-azido-3'-deoxythymidine, muraglitazar, estradiol (17-OH), and ethinyl estradiol (17-OH) were all found to show similar rates of metabolism regardless of UGT1A1 genotype. Interestingly, muraglitazar (UGT1A3 substrate) showed an inverse correlation with glucuronidation of UGT1A1 substrates. These genotyped microsomes should provide a useful tool to allow a more comprehensive prediction of UGT1A1 metabolism of a new drug and gain insight into the effect of the UGT1A1*28 polymorphism.

Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with corresponding data obtained in wild-type mice. Total brain-to-plasma (B/P) ratios for the CNS agents ranged from 0.060 to 24. Of the 34 CNS-active agents, only 7 demonstrated B/P area under the plasma concentration curve ratios between P-gp knockout and wild-type mice that did not differ significantly from unity. Most of the remaining drugs demonstrated 1.1- to 2.6-fold greater B/P ratios in P-gp knockout mice versus wild-type mice. Three, risperidone, its active metabolite 9-hydroxyrisperidone, and metoclopramide, showed marked differences in B/P ratios between knockout and wild-type mice (6.6- to 17-fold). Differences in B/P ratios and cerebrospinal fluid/plasma ratios between wild-type and knockout animals were correlated. Through the use of this model, it appears that most CNS-active agents demonstrate at least some P-gp-mediated transport that can affect brain concentrations. However, the impact for the majority of agents is probably minor. The example of risperidone illustrates that even good P-gp substrates can still be clinically useful CNS-active agents. However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect.