Nonsteroidal Dissociated Glucocorticoid Agonists Containing Azaindoles as Steroid A-Ring Mimetics

Abstract

Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.

Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

“…To synthesize the 5-fluoro derivative of the DHBF-7-carboxamide, we first attempted to launch the 5-fluoro substituent by a reported method 41 in which nitration at the 5-position of the DHBF was carried out (as mentioned previously), followed by its reduction using a Pd/C catalyst, to yield 5-amino-DHBF compound 18a (Scheme 3). The diazonium tetrafluoroborate salt of 18a was prepared by adding aqueous sodium nitrite solution into a mixture of 5-amino-DHBF, hydrochloric acid, and tetrafluoroboric acid in THF at −15 °C.…”

Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate

“…16 However, it was assumed that this moiety is also primarily responsible for the potent CYP inhibition and hERG channel inhibition observed. The effect of substitution on the azaindole ring system had not been examined previously.…”

“…A limited structure−actvity relationship (SAR) study of Dring substitution had been performed previously using the unsubstituted 6-azaindole; 16 however, to allow for greater flexibility with regard to potency as well as metabolic stability, more drastic changes on the D-Ring were examined using the potent and metabolically stable 5-morpholinyl substituted 6-azaindole. Some historic D-ring mimetics were re-examined: The unsubstituted phenyl comparator 20 showed good agonist efficacy (Table 3).…”

“…However, the translation of in vitro dissociation markers to preclinical in vivo parameters in mouse models had been previously established with tool compounds from this series and was expected to apply to these ■ EXPERIMENTAL PROCEDURES Synthesis. All compounds (except 9) described herein have been synthesized following the general scheme outlined in previous publications and summarized in Scheme 1: 16,18 A substituted halogenated aminopyridine 5 undergoes a Sonogashira coupling with the alkyne 6, and the coupling product is cyclized under basic conditions to the azaindoles 7. 20 The majority of the synthetic effort was spent on generating the required substituted alkynes and substituted pyridines, where required, compounds were modified further after the key coupling/cyclization sequence.…”

“…It is known that all GR activity in this class of compounds resides in the (R)-isomers. 16 Methods. Assay descriptions can be found in the Supporting Information.…”