Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.
Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections.
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States. Electronic address: sameer.kawatkar@astrazeneca.com.
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Kawatkar
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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M
Gagnon
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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Hoesch
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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Tiong-Yip
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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Johnson
Discovery Sciences, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
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Ek
Discovery Sciences, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
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Nilsson
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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Lister
Discovery Sciences, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
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Olsson
Discovery Sciences, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, United States.
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Patel
AstraZeneca Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA, United States.
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Yu
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D012229:Rhinovirus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D001384:Azetidines; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; C082735:azetidine; D011392:Proline; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
3C protease; Human rhino virus; Rupintrivir