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3,5-Disubstituted-indole-7-carboxamides as IKK? Inhibitors: Optimization of Oral Activity via the C3 Substituent.

ABSTRACT: I?B kinase ? (IKK? or IKK2) is a key regulator of nuclear factor kappa B (NF-?B) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

SUBMITTER: Kerns JK

PROVIDER: S-EPMC6295857 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

Kerns Jeffrey K JK Busch-Petersen Jakob J Fu Wei W Boehm Jeffrey C JC Nie Hong H Muratore Michael M Bullion Ann A Lin Guoliang G Li Huijie H Davis Roderick R Lin Xichen X Lakdawala Ami S AS Cousins Rick R Field Rita R Payne Jeremy J Miller David D DD Bamborough Paul P Christopher John A JA Baldwin Ian I Osborn Ruth R RR Yonchuk John J Webb Edward E Rumsey William L WL

ACS medicinal chemistry letters 20181030 12

IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity. ...[more]

PMID: 30613320

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