ABSTRACT
Using appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH2)nOH are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive inotropic activity. Compound 12 is almost 10 times more active than forskolin (EC50 = 0.002 microgram/ml).].
Subject(s)
Colforsin/analogs & derivatives , Colforsin/chemical synthesis , Heart/drug effects , Myocardial Contraction/drug effects , Acylation , Animals , Blood Pressure/drug effects , Colforsin/chemistry , Colforsin/pharmacology , Guinea Pigs , Heart/physiology , Heart Atria , Hydroxylation , In Vitro Techniques , Models, Molecular , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
Using the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7 beta-hydroxyacetyl-7 beta-deacetyl forskolin or 6 beta-hydroxyacetyl forskolin, a number of water soluble omega-amino acyl derivatives were synthesized. Two such compounds 6 and 18 showed better in vitro activity but failed to show in vivo activity.
Subject(s)
Blood Pressure/drug effects , Colforsin/analogs & derivatives , Colforsin/chemical synthesis , Myocardial Contraction/drug effects , Acetylation , Animals , Cats , Colforsin/chemistry , Colforsin/pharmacology , Guinea Pigs , Heart/drug effects , Heart/physiology , Heart Atria , Hydroxylation , In Vitro Techniques , Indicators and Reagents , Myocardial Contraction/physiology , Solubility , Structure-Activity Relationship , WaterABSTRACT
Ester analogues of methyl-2-(4-(2-piperidinoethoxy)benzoyl)-benzoate hydrochloride (pitofenone) (2) were prepared with an aim to find a more potent and metabolically stable antispasmodic compound. The compounds were evaluated for their in vitro and in vivo antispasmodic activity, and stability to in vitro enzymatic hydrolysis. Of the compounds synthesised, HL 752 (21) showed the most potent and long-lasting antispasmodic activity and was selected as the candidate for clinical development.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Parasympatholytics/chemical synthesis , Parasympatholytics/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Benzoates/metabolism , Benzophenones/chemical synthesis , Benzophenones/metabolism , Benzophenones/pharmacology , Dogs , Drug Stability , Esters/metabolism , Esters/pharmacology , Female , Guinea Pigs , Hydrolysis , Ileum/drug effects , In Vitro Techniques , Male , Parasympatholytics/metabolism , Piperidines/metabolismABSTRACT
8,13-Epoxy-6 beta-(piperidinoacetoxy)-1 alpha,7 beta, 9 alpha-trihydroxy-labd -14en-11-one (HL 706, CAS 114376-11-3) is a water soluble derivative of forskolin with positive inotropic and vasodilating properties. In both in vitro and in vivo preparations, it exhibited significant positive inotropic activity with concomitant increase in heart rate and decrease in mean blood pressure. Though its potency is lower than that of forskolin, its duration of action is more prolonged. In conscious dog experiments, HL 706, administered orally, also showed a dose related increase in LV dP/dtmax. A significant reversal of cardiac failure was attained in anaesthetised dogs subjected to propranolol induced cardiac insufficiency. HL 706, like forskolin increased cAMP by virtue of its adenylate cyclase stimulant activity. Through increase in cAMP it also exhibited non-specific smooth muscle relaxant activity in isolated vascular and ileal preparations. Its therapeutic ratio is quite favourable.