Discovery of Cyclophilin Inhibitor NIM811 as a Novel Therapeutic Agent for HCV

From Chemical Tools to Clinical Medicines: Nonimmunosuppressive Cyclophilin Inhibitors Derived from the Cyclosporin and Sanglifehrin Scaffolds

“…Treatment of HCV with cyclophilin inhibitors has been very promising however. Three compounds, NIM811 ( 7 , Figure ), alisporivir ( 8 , Figure ), SCY-635 ( 9 , Figure ), have been investigated in clinical trials, and each has demonstrated therapeutic efficacy . Several cyclophilins contribute to the HCV viral life cycle, , and strong evidence indicates that cyclophilin A interacts with the viral NS5A protein to stimulate the replication of the RNA genome. , In contrast to most direct antivirals, significant resistance to cyclophilin inhibitors is rarely observed, and cyclophilin inhibitors are potent across all HCV genotypes. , …”

“…Previous studies with 1 had revealed that appropriate substitution of the [Gly] 3 -group , or the addition of small hydrophobic elements to the [Leu] 4 -residue of 1 improved cyclophilin binding by increasing the population of the cyclosporin binding conformer. This information led to the investigation of the anti-HIV activity of a series of nonimmunosuppressive cyclosporins that had greater affinity for cyclophilin A than 1 itself. , Representative analogues [( d )-MeSer] 3 -[(4-OH)-MeLeu] 4 -CsA ( 6 , Figure ) and [isoleucine] 4 -CsA ( 7 , NIM-811, Figure ) were found to be inhibitors of HIV viral amplification in cellular assays and essentially devoid of immunosuppressive activity. Interestingly, while 6 was 4-fold more potent than 7 in binding assays, it was less potent in the anti-HIV cellular assay.…”

“…The lead compound from these initial studies, 7 , has higher affinity for cyclophilin A than 1 . This inhibitor has been studied clinically as an HCV medicine, and it has also been employed in a number of animal and cellular models of disease.…”

“…This information led to the investigation of the anti-HIV activity of a series of nonimmunosuppressive cyclosporins that had greater affinity for cyclophilin A than 1 itself. 81,82 Representative analogues [(D)-MeSer] 3 -[(4-OH)-MeLeu] 4 -CsA (6, 81 Figure 5) and [isoleucine] 4 -CsA (7, 84 NIM-811, Figure 5) were found to be inhibitors of HIV viral amplification in cellular assays and essentially devoid of immunosuppressive activity. Interestingly, while 6 was 4-fold more potent than 7 in binding assays, it was less potent in the anti-HIV cellular assay.…”