- Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310
-
Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profil
- Safina, Brian S.,McKerrall, Steven J.,Sun, Shaoyi,Chen, Chien-An,Chowdhury, Sultan,Jia, Qi,Li, Jun,Zenova, Alla Y.,Andrez, Jean-Christophe,Bankar, Girish,Bergeron, Philippe,Chang, Jae H.,Chang, Elaine,Chen, Jun,Dean, Richard,Decker, Shannon M.,Dipasquale, Antonio,Focken, Thilo,Hemeon, Ivan,Khakh, Kuldip,Kim, Amy,Kwan, Rainbow,Lindgren, Andrea,Lin, Sophia,Maher, Jonathan,Mezeyova, Janette,Misner, Dinah,Nelkenbrecher, Karen,Pang, Jodie,Reese, Rebecca,Shields, Shannon D.,Sojo, Luis,Sheng, Tao,Verschoof, Henry,Waldbrook, Matthew,Wilson, Michael S.,Xie, Zhiwei,Young, Clint,Zabka, Tanja S.,Hackos, David H.,Ortwine, Daniel F.,White, Andrew D.,Johnson,Robinette, C. Lee,Dehnhardt, Christoph M.,Cohen, Charles J.,Sutherlin, Daniel P.
-
-
Read Online
- Improved Synthesis of the Nav1.7 Inhibitor GDC-0276 via a Highly Regioselective SNAr Reaction
-
The development of a redesigned and improved second-generation synthesis of the Nav1.7 inhibitor GDC-0276 based on experience gained from a fit-for-purpose first-generation synthesis will be described. The first-generation synthesis proceeded via a regioselective SNAr reaction on the advanced starting material t-butyl 5-chloro-2,4-difluorobenzoate with 1-adamantanemethanol. In the newly developed second-generation synthesis, the much improved regioselective SNAr reaction was performed on the readily available starting material 1-chloro-2,4-difluorobenzene, followed by installation of the carboxylate group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki-Miyaura cross-coupling reaction was then telescoped directly into a phase-transfer-catalyzed ester hydrolysis. Amidation of the resulting acid intermediate with 1-azetidine sulfamide in turn provided GDC-0276 in high overall yield and purity on a 100 kg scale.
- Stumpf, Andreas,Cheng, Zhigang Ken,Beaudry, Danial,Angelaud, Remy,Gosselin, Francis
-
-
Read Online
- Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity
-
Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.
- Sun, Shaoyi,Jia, Qi,Zenova, Alla Y.,Wilson, Michael S.,Chowdhury, Sultan,Focken, Thilo,Li, Jun,Decker, Shannon,Grimwood, Michael E.,Andrez, Jean-Christophe,Hemeon, Ivan,Sheng, Tao,Chen, Chien-An,White, Andy,Hackos, David H.,Deng, Lunbin,Bankar, Girish,Khakh, Kuldip,Chang, Elaine,Kwan, Rainbow,Lin, Sophia,Nelkenbrecher, Karen,Sellers, Benjamin D.,Dipasquale, Antonio G.,Chang, Jae,Pang, Jodie,Sojo, Luis,Lindgren, Andrea,Waldbrook, Matthew,Xie, Zhiwei,Young, Clint,Johnson, James P.,Robinette, C. Lee,Cohen, Charles J.,Safina, Brian S.,Sutherlin, Daniel P.,Ortwine, Daniel F.,Dehnhardt, Christoph M.
-
-
Read Online
- Chemical Compounds
-
The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein Ar1, X, R1, R2, R3, R4 and R5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.
- -
-
Page/Page column 46
(2012/01/15)
-
- CHEMICAL COMPOUNDS
-
The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein Het1, X, R1, R2, R3, R4 and R5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain
- -
-
Page/Page column 55
(2012/01/15)
-