The alkyl group at C was examined and it had been established that tiny alkyl groups gave inferior effects as in comparison to greater alkyl groups. For example, methyl substituted pyrazole a was only . and . lM versus Bcl and Bcl xL, respectively whereas, butyl substituted pyrazole b showed practically fold improvement against both proteins . Alteration from the ethyl ester on the pyrazole C position also drastically impacted Bcl and Bcl xL action. By way of example, acid c noticed more enhancements in both Bcl and Bcl xL action . Alcohol d was optimum providing an IC of nM for Bcl and nM for Bcl xL. Substitution with the pyrazole N aryl group was studied extensively. Compact alkoxy substituents within the para position with the pyrazole N phenyl ring have been typically tolerated . Addition of a more substantial, more lipophilic phenoxy group from the meta and para positions was examined. Even though both analogs gave enhanced action versus Bcl , only the para substitution was tolerated for Bcl xL.
Encouraged by the improved dual inhibition demonstrated by phenyl ether g, we examined this lead further. As observed prior to, reduction in the ethyl ester to offer alcohol h was nicely tolerated. Addition of a chloride for the phenoxy ring gave an additional boost in activity. The chlorophenyl derivative j was superior on the chlorophenyl analog i inhibiting Tyrphostin AG 1296 Bcl with an IC of nM and Bcl xL with an IC of nM. Replacement of your phenoxy group with butoxy gave a modest reduction in Bcl and Bcl xL exercise. Elimination on the ether linker to give biphenyl l was properly tolerated and inhibited Bcl and Bcl xL with IC?s of and nM, respectively. Recognizing that inhibitors of protein protein interactions are inclined to be rather lipophilic with higher clogP?s, we examined appending alcohols for the pyrazole N phenyl ring to enhance aqueous solubility and develop far more drug like leads.
To that end, para alcohols m and n have been created and, gratifyingly, the Telaprevir appended alcohols were also properly accommodated by the two Bcl and Bcl xL. A meta substituted alcohol o was somewhat less energetic than its para counterparts. Following we turned our focus to SAR in the tetrahydroisoquinoline ring . Borrowing from our prior practical experience with substituted THIQs, we ready alcohol p. As anticipated, this compound demonstrated a marked improvement in Bcl potency relative on the unsubstituted THIQ d, making a potent dual inhibitor of Bcl and Bcl xL. Introduction of amine substituted THIQ q was also very well tolerated offering IC?s against Bcl and Bcl xL of and nM, respectively.
Lastly, SAR on the acylsulfonamide was explored . Replacement within the aromatic naphthyl ring which has a trimethylsilylethyl group was found for being detrimental for Bcl activity , but inconsequential with regards to Bcl xL exercise. The simple ethyl acylsulfonamide was established to get less potent for both enzymes.
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