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SUMMARY:The Discovery of PAXLOVID - Royal Society of Chemistry BMCS Lectur
 e 2024 - Dr Dafydd Owen - Pfizer
DTSTART:20240122T160000Z
DTEND:20240122T170000Z
UID:TALK207958@talks.cam.ac.uk
CONTACT:Chung Tu
DESCRIPTION:Small molecule inhibition of viral proteases has been a succes
 sful anti-viral therapeutic strategy in HIV and HCV. Structural insight on
  the SARS-CoV-2 main protease (Mpro) and previous small molecule experienc
 e with intravenous SARS-CoV-1 inhibitors gave a starting point for an oral
  Mpro inhibitor program in response to the COVID-19 outbreak. Designing an
 d synthesizing molecules in a peptidomimetic chemotype\, the team investig
 ated a number of cysteine traps as reversibly covalent inhibitors\, while 
 looking to confer sufficient metabolic stability and permeability to attai
 n oral bioavailability. Systematically challenging the need for hydrogen b
 ond donors throughout the pharmacophore proved a successful strategy for e
 nhancing permeability. This resulted in the discovery of PF-7321332\, the 
 first oral SARS-CoV-2 Mpro inhibitor to reach clinical development.1 \n\nP
 F-7321332 showed pan-human coronavirus activity with selectivity over huma
 n proteases. Phase 1 healthy volunteer studies will be described\, with an
 d without combination of low dose ritonavir as a pharmacokinetic enhancer.
  The preclinical work to identify PF-7321332 (now known as nirmatrelvir) a
 nd the resulting Ph1 study was the basis for a combined Ph2/3 study in hig
 h-risk patients. Nirmatrelvir/ritonavir went on to receive emergency use a
 uthorization for the treatment of high risk COVID-19 patients in the Unite
 d States as PAXLOVID in December of 2021\, just 17 months after nirmatrelv
 ir was first synthesized and received full FDA approval in May 2023.\n\nTh
 e ‘start to finish’ drug discovery story will be presented from a medi
 cinal chemist’s point of view.\n
LOCATION:BMS Lecture Theatre\, Department of Chemistry
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