title: Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.
abstract: [reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. david.m.andrews@gsk.com
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Helene
authors.initials: H
authors.lastname: Chaignot
authors.forename: Barry A
authors.initials: BA
authors.lastname: Coomber
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: S Lucy
authors.initials: SL
authors.lastname: Hind
authors.forename: Martin R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Jones
authors.forename: Gail
authors.initials: G
authors.lastname: Mills
authors.forename: J Ed
authors.initials: JE
authors.lastname: Robinson
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Skarzynski
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Slater
authors.forename: Donald O'N
authors.initials: DO
authors.lastname: Somers
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D004791:Enzyme Inhibitors; D007769:Lactams; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases