PKA, LOG-P AND MEDCHEM CLOGP FRAGMENT VALUES OF ACIDIC HETEROCYCLIC POTENTIAL BIOISOSTERES

被引:36
作者
LIPINSKI, CA
FIESE, EF
KORST, RJ
机构
[1] Pfizer Central Research, Groton, Connecticut
来源
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS | 1991年 / 10卷 / 02期
关键词
BIOISOSTERES; ACIDIC 5-MEMBERED HETEROCYCLES; LOG-P; RP-HPLC; MEDCHEM CLOGP; PKA;
D O I
10.1002/qsar.19910100205
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Log P values have been measured for twenty phenyl and benzyl five membered heterocycles and alicyclic analogs that might function as acidic bioisosteres. pKa's have been measured by potentiometric titration in water and 1:1 dioxane-water. From this experimental data, twelve missing fragmental CLOGP values are derived for use in calculating Log P values according to the Pomona College MedChem program. Log P values of some of the simple benzyl and phenyl heterocycles are compared to those measured for four clinically used drugs containing the same acidic moieties. Sulfonyl urea and acyl sulfonamide moieties have similar pKa and Log P values suggesting that these groups might be explored as bioisosteres.
引用
收藏
页码:109 / 117
页数:9
相关论文
共 18 条
[1]   CIGLITAZONE, A NEW HYPOGLYCEMIC AGENT .1. STUDIES IN OB/OB AND DB/DB MICE, DIABETIC CHINESE HAMSTERS, AND NORMAL AND STREPTOZOTOCIN-DIABETIC RATS [J].
CHANG, AY ;
WYSE, BM ;
GILCHRIST, BJ ;
PETERSON, T ;
DIANI, AR .
DIABETES, 1983, 32 (09) :830-838
[2]  
CLARKE FH, 1987, J PHARM SCI, V8, P611
[3]   RELATIONSHIPS BETWEEN HYDROPHOBIC (LIPOPHILIC) PROPERTIES OF BASES AND THEIR RETENTION IN REVERSED-PHASE LIQUID-CHROMATOGRAPHY USING AQUEOUS METHANOL MOBILE PHASES [J].
HAFKENSCHEID, TL ;
TOMLINSON, E .
JOURNAL OF CHROMATOGRAPHY, 1984, 292 (02) :305-317
[4]  
HANSCH C, 1974, INTRASCI CHEM REP, V8, P17
[5]   PRINCIPLES OF METHOD SELECTION IN PARTITION STUDIES [J].
HERSEY, A ;
HILL, AP ;
HYDE, RM ;
LIVINGSTONE, DJ .
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS, 1989, 8 (04) :288-296
[6]   MEDICINAL CHEMISTRY OF ALDOSE REDUCTASE INHIBITORS [J].
LARSON, ER ;
LIPINSKI, CA ;
SARGES, R .
MEDICINAL RESEARCH REVIEWS, 1988, 8 (02) :159-186
[7]   PARTITION COEFFICIENTS AND THEIR USES [J].
LEO, A ;
HANSCH, C ;
ELKINS, D .
CHEMICAL REVIEWS, 1971, 71 (06) :525-+
[8]  
LEWIS SJ, 1983, QUANT STRUCT-ACT REL, V2, P1
[9]  
Lipinski C. A., 1986, ANNU REP MED CHEM, V27, P283, DOI 10.1016/S0065-7743(08)61137-9
[10]   ACIDIC ISOSTERE DESIGN - SYNTHETIC STRATEGIES AND RECENT PROGRESS IN UNDERSTANDING ELECTRONIC-PROPERTIES AND METABOLIC STABILITY [J].
LIPINSKI, CA ;
CHENARD, BL .
PESTICIDE SCIENCE, 1990, 29 (02) :227-240