Alzheimer's disease (AD) is one of the diseases that seriously threaten human life and health. Currently, the exact pathological mechanism of the disease is still unknown, and there are no drugs that can terminate or reverse the pathological process, which have limited the discovery of AD-related targets and the development of drugs that can effectively treat AD. However, with the deepening research on the molecular mechanism of the disease and the development of computers and artificial intelligence, some potential targets of AD have been discovered and their structures have been analyzed, and at the same time, the paradigm of drug discovery and development by chemical means has been continuously expanded, which has provided medicinal chemists with a variety of methods and strategies for designing new compounds and thus synthesizing new small molecules that can be effective in treating AD. In this paper, we summarize four widely accepted hypotheses on the pathogenesis of AD and the medicinal chemistry strategies for small-molecule drug discovery and development, based on the new research results in recent years.

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC50) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC50 values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC50, 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1.

Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, 24) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, 3). The introduction of aromatic methylene ethers α to the carboxylic acid moiety significantly enhanced the antiviral profile, with additional inhibitory effects observed toward the A364V mutation, the primary resistance mutation emerging in response to selective pressure by MIs. Structure-activity optimization led to the invention of VH-937, which combined the best overall antiviral profile with pharmacokinetic properties in animal models. These properties indicate the potential for infrequent dosing, a finding confirmed in initial clinical studies in humans that suggests its potential as a once-weekly dosing agent.

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 CH2F 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 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 EC50 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.

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 (EC50 <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.

Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Na(v)1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNa(v)1.7 IC50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Na(v)1.7 inhibitors to treat pain.

The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.

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.

ABSTRACT BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC 50 ], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library ( n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC 50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC 50 s similar to those for the wild-type virus. A 5.4-fold reduction in EC 50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.

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.

Objective To study the subacute inhalation toxicity of Ivermectin TC, and obtain its non-observed adverse effect level(NOAEL).Methods It was performed on the doses of Ivermectin TC 190, 380, 750 mg/m3, the solvent control group (0.03%Tween-80 solution) , the control group and additional group ( there were 6 female and 6 male Sprague-Dawley rats for each group) .The animals inhaled with nose-only exposure for 4 weeks (4 h/d, 5 d/week) .The additional group should be observed another 14 days after exposing.At the end of experiment, the rats were killed, the routine and biochemical detection, the body weight and organ to body weight ratios were all measured.Results In the high exposure group, clinical signs of rats included hair fluffy, dull, salivation, tremors were recorded at the exposure period;in female rats, feed efficiency was decreased, ALT and liver to body weight ratio were increased; in male rats, BUN and ALT were increased, CHOL and body weight for the 4th week were decreased.Histopathological examinations revealed that swelling in the liver cell was seen in some female rats at high exposure group.Conclusion The results suggested that the NOAEL of Ivermectin TC in SD rats was 380 mg/m3(4 h/d for 28 days).

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).