title: Design and synthesis of pyrrolidine-5,5'-trans-lactams (5-oxo-hexahydropyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 4. Antiviral activity and plasma stability.
abstract: A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.
authors.affiliation: Department of Medicinal Chemistry CVU UK, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom. alan.d.borthwick@gsk.com
authors.forename: Alan D
authors.initials: AD
authors.lastname: Borthwick
authors.forename: Dave E
authors.initials: DE
authors.lastname: Davies
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ertl
authors.forename: Anne M
authors.initials: AM
authors.lastname: Exall
authors.forename: Terry M
authors.initials: TM
authors.lastname: Haley
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Hart
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Jackson
authors.forename: Nigel R
authors.initials: NR
authors.lastname: Parry
authors.forename: Angela
authors.initials: A
authors.lastname: Patikis
authors.forename: Naimisha
authors.initials: N
authors.lastname: Trivedi
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Weingarten
authors.forename: James M
authors.initials: JM
authors.lastname: Woolven
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology*; D004285:Dogs; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005123:Eye / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology*; D013058:Mass Spectrometry; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D007769:Lactams; D011480:Protease Inhibitors; D011758:Pyrroles; D012697:Serine Endopeptidases; C071910:assemblin; D015774:Ganciclovir