Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second ...generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Nle4,dPhe7-α-MSH (NDP-MSH), a highly potent analogue of α-melanocyte-stimulating hormone (α-MSH), possesses nanomolar efficacies at all the melanocortin receptor subtypes except the MC2R. Evaluation ...of the melanocortin “message” sequence of Nle4,dPhe7-α-MSH was performed on the human melanocortin receptor subtypes designated hMC1, hMC3R, hMC4R, and hMC5R. Tetrapeptides and tripeptides were stereochemically modified to explore topochemical preferences at these receptors and to identify lead peptides possessing agonist activity and subtype selectivity. Four peptides were discovered to only bind to the hMC1 and hMC4 receptor subtypes. The tetrapeptide Ac-His-dPhe-Arg-Trp-NH2 (1) possessed 0.6 μM binding affinity at the hMC1R, 1.2 μM binding affinity at the hMC4R, and agonist activity at both receptors. The tripeptides Ac-dPhe-Arg-Trp-NH2 (6) and Ac-dPhe-Arg-dTrp-NH2 (7) possessed 2.0 and 9.1 μM binding affinities, respectively, only at the hMC4R, and both compounds effected agonist activity. The tetrapeptide Ac-His-Phe-Arg-dTrp-NH2 (4) possessed 6.3 μM affinity and full agonist activity at the hMC1R, while only binding 7% at the hMC3R, 36% at the hMC4R, and 11% at the hMC5R at a maximal concentration of 10 μM. These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized. Additionally, this study identified the simplest structural agonists for the hMC1R and hMC4R receptors reported to date.
A coumarin-based prodrug system has been recently developed in our laboratory for the preparation of esterase-sensitive prodrugs of amines, peptides, and peptidomimetics. The drug release rates from ...this prodrug system were found to be dependent on the structural features of the drug moiety. In certain cases, the release can be undesirably slow for drugs that are secondary amines with relatively high pKa's. Aimed at finding ways to manipulate the release rates to suit the need of different drugs, we have examined the effect of the phenyl ring substitutions on the release kinetics of such prodrugs and found that appropriately positioned alkyl substituents on the phenyl ring could help to facilitate the release by as much as 16-fold. Therefore, introduction of alkyl substituents on the phenyl ring should allow us to manipulate the release rates and, therefore, time profiles for different drugs.
HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The ...success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K i* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir®
1 bound to the NS3 protein suggest that expansion into the S4 ...pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4
tert-butyl with a cyclohexylmethyl ligand led to inhibitor
2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine
38 and sulfone analogues
52 and
53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Systematic analysis of fragment derivatives of the superpotent α-MSH analogue, Ac-Ser-Tyr-Ser-Nle
4-Glu-His-
dPhe
7-Arg-Trp-Gly-Lys-Pro-Val-NH
2 (NDP-MSH), led to the discovery of tripeptide agonists ...possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-
dPhe-Arg-
dTrp-NH
2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6–9) “active site”. The tripeptides Ac-
dPhe-Arg-Trp-NH
2, Ac-
dPhe-Arg-
dTrp-NH
2, and Ac-
dPhe-
dArg-Trp-NH
2 stereochemical combinations require only Phe
7-Xaa
8-Trp
9, whereas Ac-
dPhe-
dArg-
dTrp-NH
2, Ac-Phe-Arg-
dTrp-NH
2, and Ac-Phe-Arg-Trp-NH
2 additionally require His
6 for minimal biological activity. Ac-
dPhe-Arg-
dTrp-NH
2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Predicting customer churn to retain existing customers is a hot topic both in the world of academia and business today. One of them is research the prediction of churn based on customer emotions. ...Emotion is an important catalyst that affects customers in the process of purchasing services, customer satisfaction in goods and services products, and assessing the level of customer loyalty to companies in the future. Bayesian Belief Network (BBN) will be used in the construction of a churn prediction model that is based on four types of happy, sad, angry, and fear emotions. The results showed that the utilization of human emotional voice classification as a variable in churn prediction can provide predictive results on the Bayesian Belief Network with a churn value of 60% and not churn of 40%.
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