Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.
[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.
Andrews
David M
DM
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. david.m.andrews@gsk.com
Chaignot
Helene
H
Coomber
Barry A
BA
Good
Andrew C
AC
Hind
S Lucy
SL
Johnson
Martin R
MR
Jones
Paul S
PS
Mills
Gail
G
Robinson
J Ed
JE
Skarzynski
Tadeusz
T
Slater
Martin J
MJ
Somers
Donald O'N
DO
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
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