GS-9620 by Gilead Sciences and BMS-791325 by Bristol-Myers Squibb | Chemical & Engineering News
Volume 90 Issue 16 | p. 43
Issue Date: April 16, 2012

GS-9620 by Gilead Sciences and BMS-791325 by Bristol-Myers Squibb

Medicinal chemists debut five drug candidates and describe their discovery.
Department: Science & Technology
Keywords: Medicinal chemistry, organic chemistry, ACS meetings, pharma, biotech, hepatitis, cancer, diabetes, migraine
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From left) Paul Hrvatin, Michael Graupe, Paul Roethle, Halcomb, Ryan McFadden, Lee Chong, Jennifer Zhang
Credit: Courtesy Gilead Sciences
Gilead team who developed GS-9620  (From left) Paul Hrvatin, Michael Graupe, Paul Roethle, Halcomb, Ryan McFadden, Lee Chong, Jennifer Zhang
 
From left) Paul Hrvatin, Michael Graupe, Paul Roethle, Halcomb, Ryan McFadden, Lee Chong, Jennifer Zhang
Credit: Courtesy Gilead Sciences

Randall L. Halcomb, director of medicinal chemistry at Gilead Sciences in Foster City, Calif., revealed the structure of GS-9620, a potential drug for chronic hepatitis B as well as hepatitis C. The molecule is an orally administered agonist of Toll-like receptor 7 (TLR7), a receptor on immune cells that responds to virusderived RNA. Gilead’s scientists had a specific reason for targeting the immune system, Halcomb told C&EN. “In general when a hepatitis B patient goes on to therapy, they’re on antivirals for the rest of their lives,” Halcomb said. The team’s goal in developing an immune system stimulant was to make lifelong treatment unnecessary. “After a short-term course or treatment with such a drug, the hepatitis B virus might be either controlled or eliminated,” he said.

In addition, the Gilead team thought a pill might sidestep the side effects of established hepatitis treatments such as ribavirin and interferon, an injected therapy that can lead to flulike symptoms. A pill “would get to the liver, where hepatitis lives,” without “floating around throughout the body” first as an injectable therapy does, Halcomb said.

Gilead’s chemists started from published molecules, including Sumitomo Pharmaceuticals’ SM360320, with weak TLR7 agonist activity (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0813037106). To guide their optimization efforts, the team measured concentrations of interferon produced by white blood cells, a sign of immune system stimulation, in response to a drug candidate. As they searched for a molecule to advance to clinical trials, they examined benzyl side chains with a range of pKa’s from acidic to basic, and learned that a basic amine was important for TLR7 agonist activity. Their efforts culminated in GS-9620.

For late-stage testing in animals, Gilead’s scientists relied on woodchucks, which have a liver disease that both genetically resembles human hepatitis B and progresses in a similar way to the human ailment. They demonstrated that a four-week treatment with oral doses of GS-9620 enabled the animals to control the virus for a 20-week period. This suggests that a finite course of hepatitis B treatment might be possible, Halcomb told C&EN. “We’re hoping to replicate that in humans.”

In a Phase Ia clinical trial in healthy volunteers, GS-9620 elicited an immune response comparable to that of interferon without also causing flulike symptoms. The molecule is currently in Phase Ib clinical trials, where its safety and pharmacokinetics are being tested in patients with hepatitis B or hepatitis C.

[+]Enlarge
Seated, from left) Piyasena Hewawasam, Min Ding, Dawn Parker, Mengping Liu; (middle, from left) Julie Lemm, Zhong Yang, Yong Tu, Lenore Pelosi, Xiaoliang Zhuo, Xiaofan Zheng, Karen Rigat, Alicia Regueiro-Ren, Meanwell, Katherine Grant-Young; (back, from left) John Bender, Kap-Sun Yeung, Susan Roberts, John Kadow, Scott Martin, Robert Gentles, Ying-Kai Wang.
Credit: Courtesy of Bristol-Myers Squibb
Bristol-Myers Squibb team behind BMS-791325  (Seated, from left)  Piyasena Hewawasam, Min Ding, Dawn Parker, Mengping Liu (Middle, from left) Julie Lemm, Zhong Yang, Yong Tu, Lenore Pelosi, Xiaoliang Zhuo, Xiaofan Zheng, Karen Rigat, Alicia Regueiro-Ren, Meanwell,  Katherine Grant-Young (Back, from left)  John Bender, Kap-Sun Yeung, Susan Roberts, John Kadow, Scott Martin, Robert Gentles, Ying-Kai Wang
 
Seated, from left) Piyasena Hewawasam, Min Ding, Dawn Parker, Mengping Liu; (middle, from left) Julie Lemm, Zhong Yang, Yong Tu, Lenore Pelosi, Xiaoliang Zhuo, Xiaofan Zheng, Karen Rigat, Alicia Regueiro-Ren, Meanwell, Katherine Grant-Young; (back, from left) John Bender, Kap-Sun Yeung, Susan Roberts, John Kadow, Scott Martin, Robert Gentles, Ying-Kai Wang.
Credit: Courtesy of Bristol-Myers Squibb

Nicholas A. Meanwell, executive director of discovery chemistry at Bristol-Myers Squibb, presented the story behind BMS-791325, a potential hepatitis C drug that inhibits the hepatitis C nonstructural protein 5B (NS5B) replicase, a polymerase enzyme responsible for copying viral RNA.

Meanwell reiterated that a big goal for researchers in the hepatitis field is to eliminate patients’ need for interferon and ribavirin. To that end BMS has focused on small-molecule combination therapies. For example, in a Phase IIa clinical trial, a combination of two BMS drug candidates, daclatasvir, which targets the NS5A replication complex, and asunaprevir, a hepatitis C protease inhibitor, lowered hepatitis C virus to undetectable levels after 24 weeks (Hepatology, DOI: 10.1002/hep.24724).

Early in its replicase inhibitor program, BMS took inspiration from an indole scaffold, first reported by researchers at Boehringer Ingelheim, that bound to an allosteric site in the replicase (Bioorg. Med. Chem. Lett., DOI: 10.1016/j.bmcl.2011.03.067). The BMS scientists found that after constraining the indoles with a bridge, adding a morpholine amide to their indole core enhanced their molecules’ potency. Ultimately, to minimize off-target effects, this group was replaced with a methylated piperazine, with the substituents that had decorated the morpholine stitched together to give another ring. The BMS team added a cyclopropane to the drug candidates’ seven-membered ring to better mesh with the shape of the NS5B replicase’s allosteric binding pockets, which had been uncovered by an X-ray structure of an early inhibitor bound to the replicase. These efforts eventually led to BMS-791325.

Meanwell’s team demonstrated that BMS-791325 effectively reached the liver, the site of hepatitis C infection, in rats, dogs, and cynomolgus monkeys. Meanwell did not disclose any data from clinical studies of BMS-791325, but he told C&EN that the molecule is currently in Phase II clinical trials to evaluate its effectiveness in hepatitis C patients in combination with other agents, including daclatasvir and asunaprevir.

 
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