Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor.

A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC50 11, 2.4 × 102, 2.8 × 103, and 1.1 × 102 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.

Synthesis toward CRHR1 Antagonists through 2,7-Dimethylpyrazolo[1,5-α][1,3,5]triazin-4(3H)-one C-H Arylation.

A novel synthetic protocol for 8-aryl substituted pyrazolo[1,5-α][1,3,5]triazin-4(3H)-ones was developed employing Pd-catalyzed C-H arylation. The reaction yield was influenced by the presence of a phosphine ligand, pivalic acid, and base selection. With the use of 5-10 mol % catalyst, reactions of 2 with p- or m-substituted aryl bromides proceeded in moderate to good yields. Lower yields were observed with o-substituted aryl bromides. Using this method a precursor for MJL1-109-2, a known nonpeptide CRHR-1 antagonist, was successfully synthesized.

Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters.

Anti-cancer agents delivered to cancer cells often show multi-drug resistance (MDR) due to expulsion of the agents. One way to address this problem is to increase the accumulation of anti-cancer agents in cells via amino acid transporters. Thus, val-lapatinib and tyr-lapatinib were newly synthesized by adding valine and tyrosine moieties, respectively, to the parent anti-cancer agent lapatinib without stability issues in rat plasma. Val-lapatinib and tyr-lapatinib showed enhanced anti-cancer effects versus the parent lapatinib in various cancer cell lines, including human breast cancer cells (MDA-MB-231, MCF7) and lung cancer cells (A549), but not in non-cancerous MDCK-II cells. A glutamine uptake study revealed that both val-lapatinib and tyr-lapatinib, but not the parent lapatinib, inhibited glutamine transport in MDA-MB-231 and MCF7 cells, suggesting the involvement of amino acid transporters. In conclusion, val-lapatinib and tyr-lapatinib have enhanced anti-cancer effects, likely due to an increased uptake of the agents into cancer cells via amino acid transporters. The present data suggest that amino acid transporters may be an effective drug delivery target to increase the uptake of anti-cancer agents, leading to one method of overcoming MDR in cancer cells.

Synthesis and structural analysis of 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid as a conformationally constrained gamma-turn mimic.

An efficient asymmetric synthesis of 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid as a novel gamma-turn mimic has been achieved. Structural analysis of the gamma-amino acid derivative was carried out using (1)H NMR spectroscopy and intramolecular hydrogen bonding between side chain amides confirmed the turn structure, which had been predicted by Ab initio computational study.

Design, synthesis and evaluation of (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor.

Based on (R)-N-methyl-N-(5-azaspiro[2.4]heptan-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a core scaffold, we identified (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile [(R)-6c] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinib's 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound (R)-6c exhibited an IC50 value of 8.5 nM against JAK1 with a selectivity index of 48 over JAK2. To optimize (R)-6c as a lead compound, we performed in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Mouse and rat in vivo studies verified that (R)-6c exhibited desired efficacies in CIA and AIA models.

Novel benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors.

Our study describes the discovery of a series of highly potent hepatitis C virus (HCV) NS5A inhibitors based on symmetrical prolinamide derivatives of benzidine and diaminofluorene. Through modification of benzidine, l-proline, and diaminofluorene derivatives, we developed novel inhibitor structures, which allowed us to establish a library of potent HCV NS5A inhibitors. After optimizing the benzidine prolinamide backbone, we identified inhibitors embedding meta-substituted benzidine core structures that exhibited the most potent anti-HCV activities. Furthermore, through a battery of studies including hERG ligand binding assay, CYP450 binding assay, rat plasma stability test, human liver microsomal stability test, and pharmacokinetic studies, the identified compounds 24, 26, 27, 42, and 43 are found to be nontoxic, and are expected to be effective therapeutic anti-HCV agents.

Potent Hepatitis C Virus NS5A Inhibitors Containing a Benzidine Core.

Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.