Improvement of therapeutic index of phosphodiesterase type IV inhibitors as anti-Asthmatics.
A new series of catechol hydrazines was synthesized and their structure-activity relationship (SAR) was analyzed for developing an effective phosphodiesterase 4 (PDE4) inhibitor as an anti-asthmatic drug candidate. Among the (E)-Analogues tested using in vitro assays, 5CC showed a strong PDE4 inhibitory activity and a significantly improved rolipram binding profile compared with rolipram, a prototype PDE4 inhibitor. Moreover, from in-vivo asthma model, we observed that (E)-Analogue 5CC had a good efficacy against guinea-pig respiratory tract inflammation and bronchoconstriction, along with a remarkably reduced emetic side effect, compared with rolipram. Conclusively, (E)-Analogue 5CC seems to be a promising candidate for the development of anti-asthmatic PDE4 inhibitors.
Kim
Euikyung
E
Pharmacology and Analytical Chemistry Research, 319 Hyundai I Valley, 223-12 Sandaewon-dong, Choongwon-gu, Sungnam-si, 462-120, Kyonggi-do, Republic of Korea. ekim@postech.ac.kr
Chun
Hyung Ok
HO
Jung
Sung Hak
SH
Kim
Jong Hoon
JH
Lee
Jae Mok
JM
Suh
Byung Chul
BC
Xiang
Myung Xik
MX
Rhee
Chung K
CK
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005289:Ferrets; D006168:Guinea Pigs; D006834:Hydrazines / Q000138:chemical synthesis / Q000627:therapeutic use; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008958:Models, Molecular; D009126:Muscle Relaxation / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use*; D020889:Rolipram / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced
D018927:Anti-Asthmatic Agents; D006834:Hydrazines; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram