The alkyl group at C was examined and it had been established that minor alkyl groups gave inferior success as when compared with bigger alkyl groups. By way of 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 the two proteins . Alteration of your ethyl ester at the pyrazole C place also appreciably impacted Bcl and Bcl xL activity. For example, acid c noticed even further improvements in each Bcl and Bcl xL exercise . Alcohol d was optimum giving an IC of nM for Bcl and nM for Bcl xL. Substitution in the pyrazole N aryl group was studied extensively. Minor alkoxy substituents within the para place in the pyrazole N phenyl ring have been usually tolerated . Addition of the more substantial, even more lipophilic phenoxy group within the meta and para positions was examined. Whereas both analogs gave enhanced exercise 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 additional. As observed just before, reduction of your ethyl ester to give alcohol h was well tolerated. Addition of a chloride for the phenoxy ring gave an extra grow in activity. The chlorophenyl derivative j was superior towards the chlorophenyl analog i inhibiting Quizartinib FLT-3 inhibitor Bcl with an IC of nM and Bcl xL with an IC of nM. Substitute of the phenoxy group with butoxy gave a modest reduction in Bcl and Bcl xL action. Elimination with the ether linker to provide biphenyl l was well tolerated and inhibited Bcl and Bcl xL with IC?s of and nM, respectively. Recognizing that inhibitors of protein protein interactions usually tend to be rather lipophilic with substantial clogP?s, we examined appending alcohols to your pyrazole N phenyl ring to improve aqueous solubility and build even more drug like leads.
To that end, para alcohols m and n have been created and, gratifyingly, the CC-5013 appended alcohols were also very well accommodated by the two Bcl and Bcl xL. A meta substituted alcohol o was somewhat less lively than its para counterparts. Up coming we turned our focus to SAR of the tetrahydroisoquinoline ring . Borrowing from our former encounter with substituted THIQs, we prepared alcohol p. As anticipated, this compound demonstrated a marked improvement in Bcl potency relative to the unsubstituted THIQ d, producing a potent dual inhibitor of Bcl and Bcl xL. Introduction of amine substituted THIQ q was also well tolerated giving IC?s towards Bcl and Bcl xL of and nM, respectively.
Lastly, SAR of your acylsulfonamide was explored . Replacement on the aromatic naphthyl ring that has a trimethylsilylethyl group was discovered for being detrimental for Bcl activity , but inconsequential with regards to Bcl xL exercise. The simple ethyl acylsulfonamide was determined to be significantly less potent for the two enzymes.