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.
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.
Borthwick
Alan D
AD
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
Davies
Dave E
DE
Ertl
Peter F
PF
Exall
Anne M
AM
Haley
Terry M
TM
Hart
Graham J
GJ
Jackson
Deborah L
DL
Parry
Nigel R
NR
Patikis
Angela
A
Trivedi
Naimisha
N
Weingarten
Gordon G
GG
Woolven
James M
JM
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
D000998:Antiviral Agents; D007202:Indicators and Reagents; D007769:Lactams; D011480:Protease Inhibitors; D011758:Pyrroles; D012697:Serine Endopeptidases; C071910:assemblin; D015774:Ganciclovir