1 4/15 4/22 CC/TBDD(CADD) 5/6-1 1 5/6-2 1 4/15
BO:17-2-1-1
BO:17-2-1-1 Drug Discovery based on Genome (Information) Combinatorial Chemistry Random screening Lead Optimization target validation
Target Validation target : validation: validation
/
( ( )
not
AD.50 AD.50-220
19 ( O O O O
1803 1820 1887 1900 1928 1938 O C 3 O O O O O O O C 3 C 3 COO O O R O O 2
20 QOL O C 2 O O O O O C 2 O O COO O O COO
2 ( 2 ( Me Me ( but Me Me C ( )
(BDD) CC T O O O O O O O O C 2 O C 2 O O COO O 2 Me Me C
21 ( ) 2003
( ( )
http://hobab.fc2web.com/sub2-kesshoubangyoushu.htm
( ( ( http://hobab.fc2web.com/sub2-kesshoubangyoushu.htm
CF3 Itazigrel Me Timegadine But, without with with
CF3 Me Itazigrel Timegadine (seed: (Lead: ) 2 Lead optimization
A. Tanaka et al., J. Med. Chem., 37, 1189-1199 (1994) itazigrel CF 3 2 R 1 R 2 R 3 timegadine Me R 1 R 2 R 3 IC50, µm IC50, µm Me Me Me Et ipr Me c-hex Me -Me-piperadine morpholine imidazoline aspirin itazigrel timegadine 31 0.062 >0.1 >0.1 0.037 >1.0 0.97 >1.0 <1.0 >0.1 16 0.0056 0.031 2.0 1.2 not tested 9.1 4.8 >100 2.4 21 66 not tested >600 >300 1.5
( R 1 R 2 R 3 R 1 =Me R 2 =Me R 3 = ( O O O Cl 2 4,4'-Dimethoxybenzoin (Aldrich, 4,200/25g) Me Me Me Me Me
A. Tanaka et al., J. Med. Chem., 37, 1189-1199 (1994) itazigrel CF 3 2 R 1 R 2 R 3 timegadine Me R 1 R 2 R 3 IC50, µm IC50, µm Me Me Me Et ipr Me c-hex Me -Me-piperadine morpholine imidazoline aspirin itazigrel timegadine 31 0.062 >0.1 >0.1 0.037 >1.0 0.97 >1.0 <1.0 >0.1 16 0.0056 0.031 2.0 1.2 not tested 9.1 4.8 >100 2.4 21 66 not tested >600 >300 1.5
2 R 1 R 2 R 1 R 2 IC50, µm IC50, µm Me COMe CO- 3 -py COC 2 -Ph COC 2 Me Me 0.096 0.015 >0.1 0.025 <0.1 <0.1 8.4 8.1 7.7 8.2 4.2 6.0 O C o CO-morpholine COMe CO-iPr 0.055 0.66 0.022 0.042 7.3 12 15 5.7 A. Tanaka et al., J. Med. Chem., 37, 1189-1199 (1994)
O R 1 R 2 R R 4-Me-piperadine (FR122047) 2 Me 2 Et 2 C() 2 morpholine piperadine 4-ethanolpiperadine 4-Me-homopiperadine 4-(2-hydroxyethyl)piperadine 2 C 2 -morpholine C 2 C 2-3-Py -piperadino-co-ipr IC50, µm IC50, µm 0.088 >1 <0.1 <0.01 >0.1 <0.01 >1 0.045 >0.1 >1 >1 <0.1 >1 6.2 not tested 3.0 14 >100 >100 11 6.8 4.3 9.5 8.7 20 15 A. Tanaka et al., J. Med. Chem., 37, 1189-1199 (1994)
CF3 Me Itazigrel Timegadine (seed: O Me (Lead: ) 2
( ( )
( ( ) eed Lead
1) / T 2) BDD (tructure based Drug Design) 3) (
/ T combinatorial= A1 A2 A3 B4 B5 B6 C14 C15 C16 C24 C25 C26 C34 C35 C36 A1 B4 C14 + A B 1 1
/ T T (igh Throughput creening) throughput= T(igh Throughput creening)
BDD (tructure-based Drug Design) (1 2 O O O COO COO FK633(
BDD (tructure-based Drug Design) AuroraA:
DA DA 23 )
DA DA(A,T,C,G 4 ) mra A,U,C,G ( 20
DA Fas camp
cience Jul 18 2003: 386
Connor and Ferguson-mith, 1993