N,N-DIMETHYL-(3R,4AR,5S,6AS,10S,10AR,10BS)-5-(ACETYLOXY)-3-ETHENYLDODECAHYDRO-10,10B-DIHYDROXY-3,4A,7,7,10A-PENTAMETHYL-1-OXO-1H-NAPHTHO[2,1-B]PYRAN-6-YL ESTER B-ALANINE HYDROCHLORIDE

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+).

brand name

Adele; Adehl

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).

storage

+4°C (desiccate)