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

Abstract

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.

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

“…IκB kinase β (IKKβ), a major regulator of nuclear factor κB (NF-κB), is a therapeutic target for the development of nonsteroidal anti-inflammatory agents . Kerns et al described the optimization of 3,5-disubstituted indole-7-carboxamides as inhibitors of IKKβ . Compound 35 showed promising in vitro potency and PAMPA permeability, but it suffered from moderate oral exposure and short half-life.…”

Domino Synthetic Strategy for Tetrahydrothiopyran Derivatives from Benzaldehydes, 2-Acetylfuran/2-Acetylthiophene, and Sodium Sulfide

“…1 H NMR (500 MHz, CDCl 3 ) δ 7.67 (d,1H,J = 7.8 Hz),7.54 (d,1H,J = 7.6 Hz),2H),3H),5H),2H),5.61 (d,1H,J = 2.4 Hz),5.31 (d,1H,J = 10.7 Hz),5.11 (dd,1H,J = 11.2,3.0 Hz),4.37 (d,1H,J = 10.8 Hz), 2.67−2.58 (m, 5H), 2.45 (s, 3H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 197. 6,151.8,144.6,138.3,136.4,136.02,135.98,135.1,133.8,130.72,130.70,128.0,127.8,127.7,127.4,126.8,126.5,126.4,126.1,124.0,123.0,75.9,60.8,47.9,42.8,39.5,19.7,19.3;HRMS (ESI) m/z: [M + Na] + calcd for C 28 H 26 O 2 S 3 Na 513.0987; found 513.0968.…”

“…Sulfur-containing compounds are widely applied as pesticides, medicines, and synthons playing irreplaceable roles in academic and industrial communities. − Tetrahydrothiopyran (THTP) derivatives have been testified to exhibit many pharmaceutical properties such as antibacterial, anticancer, anti-inflammatory, and antiviral activities. − In the past decades, some convenient methods for the synthesis of THTP derivatives have been developed. However, most of them suffer from a number of drawbacks such as the introduction of expensive or toxic metal catalysts, long synthesis routes, limited substrate scopes, and low yields. − These problems greatly limited their practical application.…”

RhCl3·3H2O-Catalyzed C7-Selective C–H Carbonylation of Indolines with CO and Alcohols

“…In particular, C7-carboxylated indolines or their derivatives usually display particular biological activities (Figure ). For this reason, development of effective methods for the access of C7-carboxylated indolines and derivatives thereof has been disclosed, and a host of reactions have been reported. , Conventional procedures for preparing C7-carboxylated indolines and their derivatives mainly involve commonly used organometallic reagents by direct functionalization of indoline cores or cyclization reactions to form the indoline cycles. − In recent years, transition-metal-catalyzed site-selective C–H carbonylation with CO and different nucleophiles has emerged as an attractive method enabling the straightforward synthesis of C7-carbonylated indolines or their derivatives (Scheme ). In 2012, a study on Ru 0 -catalyzd direct C7 carbonylation of N -pyridylindolines with CO and olefins appeared for accessing C7-aliphatic acyl-derived compounds (Scheme a) .…”

“…For instance, indole-7-ester 8 could be obtained via an oxidation/removal of the pyrimidyl group sequence . Thus, this methodology would be of interest for facile synthesis of those bioactive inhibitors from readily available starting materials …”