Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

Abstract

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels. KEYWORDS: HIV-1, hERG, CCR5, chemokine receptor Recently, we reported 5 on the identification of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amides (1) as a novel class of CCR5 antagonists that exhibited potent inhibition of R5 HIV-1 (BaL) replication in PBMC (Figure 1). These compounds were identified based on our initial redesign efforts of Schering C. 6 Although these compounds met most of the criteria for further development, they were found to have a significant hERG liability (also reported by the GSK 7 and Pfizer 8 groups), which we sought to mitigate by reducing the lipophilicity through the design of compounds 2 (Figure 1). The antiviral activity was used to determine a structure−activity relationship (SAR), and it was measured utilizing the R5 HIV-1 PBMC assay. 9 In addition, we also utilized a gp120/CCR5 cell fusion assay 10 as a first pass screen to select compounds for antiviral screening since the fusion data were found to be a reliable predictor of antiviral activity.On the basis of the recognition that compound 1a containing an anilino nitrogen (R 1 = phenyl) had potent antiviral activity, we reasoned that the most expedient way to address the hERG liability was to replace the substituted phenyl group on the left had side with an amide or urea that would reduce the lipophilicity 11 as measured by cLog P. Initially, the 4-methyl pyridine moiety on the top left-hand side was retained, but these compounds were substantially less potent than the corresponding thiophene analogues, 5 so the thiophene moiety was utilized for further optimization (Table 1). For example, comparison of the tetrahydropyranyl esters 1b and 2b showed that the thiophene 2b provided a 44-fold enhancement in potency as compared to the 4-methyl pyridine 1b based on CCR5 fusion inhibition. Similarly, comparison of the pyridinyl ureas 1c and 2c showed a 130-fold increase in potency for 2c as compared to the 4-methyl pyridine 1c.Several amide analogues of compound 2 were prepared (Table 2). Aside from maintaining antiviral potency, the important properties that were measured to distinguish the analogues was fusion inhibition shift in the presence of α-1-acid glycoprotein (AGP), human plasma protein binding, and hERG inhibition based on % inhibition and/or IC 50 . The simple methyl amide 2d containing the optimum 2-chloro-4,6-

Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication

“…We have recently reported our efforts to design structurally unique compounds using SCH-C as our starting point. In a systematic approach, we first modified the piperidyl-amide group and then successfully discovered several new scaffolds for the benzoxime moiety − (Figure ). Mutation studies investigated how these small molecules interact with CCR5, and, in agreement with the literature, − all of the small-molecule antagonists tested so far share a common binding site in the transmembrane region beneath ECL 2.…”

Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening

“…To guarantee maximal structural diversity, these compounds were grouped based on their chemical scaffolds and structural similarity, resulting in 39 different clusters (Table S1, Supporting Information). The most active compound from each cluster was selected, resulting in 39 training set compounds representing various chemical scaffolds. − The selected compounds were then aligned on the coordinates of MVC obtained from its crystal structure bound to the CCR5 receptor (PDB code: 4MBS) using the align.svl script in MOE . For each compound, low energy conformations were generated and the conformer with the highest alignment score was selected.…”

“…The generated pharmacophore hypotheses were validated by retrospective VS using a test set composed of 2504 compounds. The test set included 60 CCR5 inhibitors collected from the literature, − which were labeled as actives. The remaining 2444 molecules were labeled as inactives, comprising 91 biologically confirmed inactive compounds, 201 CCR5 decoys obtained from the GPCR Decoys Database (GDD), and 2152 inhibitors of different targets including GPCRs [adenosine A2a receptor (AA2A), β-1 adrenergic receptor (ADRB1), β-2 adrenergic receptor (ADRB2), C-X-C chemokine receptor type 4 (CXCR4), and dopamine D3 receptor (DRD3)] and non-GPCRs [angiotensin converting enzyme inhibitors, carbonic anhydrase inhibitors, cyclooxygenase-1 (COX-1) inhibitors, and renin inhibitors], all obtained from the GPCR Ligand Library (GLL) and Drugbank .…”

Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity

“…In this work, the key intermediate 5 was obtained by a convenient four-step procedure in moderate yields and the synthetic route was depicted in Scheme 1 : First, esterification of nicotinic acid was undertaken to yield 2 ; then, compound 2 was oxidated with 3-chloroperoxybenzoic acid (mCPBA) to afford pyridine N -Oxides 3 ; next, a nucleophilic substitution of the ortho-position of pyridine N -Oxides 3 with trimethylsilyl cyanide (TMSCN) was conducted to generate 4 [ 24 ]; finally, compound 4 was reacted with Na and NH 4 Cl in EtOH solution to get compound 5 [ 25 ].…”