Description
Colforsin daropate was launched in Japan as a treatment for acute
heart failure. It is a water-soluble and orally active 3-dimethylaminopropionyl
(daropate) derivative of forskolin, a labdane-type diterpene isolated from the root
of Coleus forskohlii. It is obtained from forskolin in 7 steps based upon a series
of protections and deprotections of the different OH groups and a key 7,8-
transacylation. Colforsin daropate is the first in its class of adenylate cyclase
activators to be marketed in the treatment of heart failure. As forskolin, it directly
stimulates adenylate cyclase thus increasing intracellular concentration of cAMP
and inhibiting calcium mobilization. As a direct consequence, it induces a
significant vasodilatation, so provides a moderate positive inotropic and
chronotropic effect. In contrast with well-established generators of cAMP
synthesis (dobutamine), Colforsin daropate maintains its action on cardiac
muscle in the severe stage even when the beta-adrenoceptor is down-regulated
in myocardium. In several clinical trials in patients with severe congestive heart
failure (CHF), Colforsin daproate improved hemodynamic symptoms of heart
failure patients without serious adverse effects.
Originator
Nippon Kayaku (Japan)
Uses
NKH 477 is a water-soluble analog of Forskolin (F701800), that is a potent activator of adenylyl cyclase, which shows some selectivity for cardiac (type V) adenylyl cyclase).
Definition
ChEBI: Colforsin daropate hydrochloride is the hydrochloride salt of colforsin daropate. It is a drug used for the treatment of acute heart failure. It directly stimulates adenylate cyclase and produces positive inotropic and vasodilator effects accompanied by the increase in cellular cAMP. It has a role as an adenylate cyclase agonist, an antihypertensive agent, a cardiotonic drug and a vasodilator agent. It contains a colforsin daropate(1+).
Biological Activity
Water-soluble analog of forskolin ([3R-(3a,4ab,5b,6b,6aa,10a,10ab,10ba)]-5-(Acetyloxy)-3-ethenyldodecahydro-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1H-naphtho[2,1-b]pyran-1-one ) that is a potent activator of adenylyl cyclase; shows some selectivity for cardiac (type V) adenylyl cyclase. Stimulates bronchodilation (EC 50 = 32.6 nM) and is an orally active potent positive chronotrope and hypotensive agent in vivo . Also available as part of the PKA Tocriset™ .
Biochem/physiol Actions
NKH 477 is a potent, orally active adenylyl cyclase activator. It is a water soluble derivative of forskolin, and dose dependentyl increases cAMP and blocks potassium-induced contraction concetrations in smooth muscle strips (IC50 = 80 nM). NKH 477 causes relaxation of histamine treated guinea pig smooth muscle (IC50 = 32 nM).
