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Harlow, United Kingdom

Fauber B.P.,Genentech | Rene O.,Genentech | De Leon Boenig G.,Genentech | Burton B.,Units 7 9 Spire Green Center | And 13 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility. © 2014 Elsevier Ltd. All rights reserved. Source


Fauber B.P.,Genentech | De Leon Boenig G.,Genentech | Burton B.,Units 7 9 Spire Green Center | Eidenschenk C.,Genentech | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors. © 2013 Elsevier Ltd. All rights reserved. Source


Fauber B.P.,Genentech | Rene O.,Genentech | Burton B.,Units 7 9 Spire Green Center | Everett C.,Genentech | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Screening a nuclear receptor compound subset in a RORc biochemical binding assay revealed a benzylic tertiary sulfonamide hit. Herein, we describe the identification of compounds with improved RORc biochemical inverse agonist activity and cellular potencies. These improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors. © 2014 Elsevier Ltd. All rights reserved. Source


Fauber B.P.,Genentech | Gobbi A.,Genentech | Savy P.,Units 7 9 Spire Green Center | Burton B.,Units 7 9 Spire Green Center | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure-activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors. © 2015 Elsevier Ltd. Source


Fauber B.P.,Genentech | Gobbi A.,Genentech | Robarge K.,Genentech | Zhou A.,Genentech | And 15 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology. © 2015 Elsevier Ltd. All rights reserved. Source

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