Cardiovascular effects of NKH477, a novel potent water-soluble forskolin derivative

Hosono, Makoto; Takahira, Takashi; Fujita, Akira; Fujihara, Ryo; Ishizuka, Osamu; Ohoi, Itaru; Tatee, Tochiro; Nakamura, Keita

doi:10.1016/0014-2999(90)93628-4

Cited by 15 publications

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“…Although the biological profile of forskolin is characterized by various pharmacological properties such as the positive inotropic, hypotensive, bronchospasmolytic and antiglaucoma activities that have been proved in vitro and in vivo using mainly laboratory animals and few humans, forskolin has not been available as an approved drug due to its low water solubility (ca. 0.001 %) [212] and low oral activity that limit its clinical usage as an intravenous formulation and an oral one, respectively [213], as well as the concern that forskolin as a nonspecific adenylyl cyclase activator may be too toxic for clinical use. Forskolin has, therefore, been considered as a useful prototype for the development of similar agents with better water solubility and more selective effects on adenylyl cyclase types.…”

Section: Second Generation Forskolin Derivativesmentioning

confidence: 99%

“…Further synthetic and structure-activity studies, such as the introduction of water-soluble substituents onto forskolin, were carried out, and of the active analogues produced, the 6-(3-dimethylaminopropionyl) forskolin hydrochloride (NKH477) (79) (see Fig. 7 in part 1) was found to be one of the more potent water-soluble forskolin derivatives [213,214,216,217]. NKH477, like forskolin, was also found to stimulate adenylyl cyclase directly and produce various cAMP-dependent pharmacological effects, for example, on cardiovascular, respiratory, renal, and immune systems [92,[218][219][220][221][222][223].…”

Section: Second Generation Forskolin Derivativesmentioning

confidence: 99%

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Plectranthus barbatus: A Review of Phytochemistry, Ethnobotanical Uses and Pharmacology – Part 2

Alasbahi

Melzig²

2010

Planta Med

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Pharmacology ! Plectranthus barbatusStudies on several extracts with various polarities obtained from different parts of P. barbatus revealed a number of pharmacological properties that may justify most of the traditional uses of P. barbatus, for example, organic extracts were reported to possess anti-inflammatory, antimicrobial [1, 2], antioxidant [3], cytotoxic [4], hypotensive [5,6], spasmolytic [7], hepatoprotective [8] and antifeedant [9] activities as well as activity against Ehrlichʼs ascites tumor in mice [10]. An alcoholic extract of the P. barbatus roots was shown to exhibit marked inhibitory action against Escherichia coli toxin-induced secretory response in rabbits and guinea pig ileal loops [11]. It has been shown that a hydroalcoholic extract of P. barbatus (880 mg/kg/day) exerted a variety of toxic effects on the different periods of pregnancy in rats; for example, in the period before embryo implantation, it caused a delay in fetal development and anti-implantation and, after embryo implantation, a delay in the development associated with maternal toxicity [12]. The water extract of P. barbatus leaves was found to exert hypoglycemic, hypotensive and antispasmodic activities [13]. It has been demonstrated that the water extract (WE) of the stems and leaves, at a dose of 1 g/kg p. o., shortened the sleeping time induced by pentobarbital by 37 %, and at a dose of 2 g/kg p. o. enhanced the intestinal transit of charcoal by 30% in mice. The WE (2 g/kg/intraduodenal) also reduced the gastric secretions (3.9 ± 1.0 to 0.5 ± 0.2 mL/4 h), and total acid secretion (34.4 ± 11.0 to 2.7 ± 0.5 mEq/L) and raised gastric pH (2.2 ± 0.3 to 6.5 ± 0.8) in rats. The treatment with WE (2 g/ kg p. o.) was also found to protect against lesions induced by ethanol or cold-restraint stress, in pylorus-ligated rats [14]. Similar results were obtained by Schultz et al. [15] who reported that the WE of the leaves (0.5-0.1 g/kg) injected into the duodenal lumen decreased the volume (62 and 76 %) and total acidity (23 and 50%) of gastric Abstract ! Plectranthus barbatus Andr. is one of the most important species of the genus Plectranthus L′ Herit. (Lamiaceae), with a wide variety of traditional medicinal uses in Hindu and Ayurvedic traditional medicine as well as in the folk medicine of Brazil, tropical Africa and China. The plant has therefore been an attractive target for intensive chemical and pharmacological studies up to now. This review presents data about the phytochemistry, ethnobotanical uses and pharmacology of Plectranthus barbatus as well as the pharmacology of its constituents. In addition to essential oil, abietane diterpenoids and 8,13-epoxy-labd-14-en-11-one diterpenoids are the main constituents found in Plectranthus barbatus. The major ethnobotanical uses are for intestinal disturbance and liver fatigue, respiratory disorders, heart diseases and certain nervous system disorders. Forskolin as one of the major constituents with its unique adenylyl cyclase activation that underlies the wide range of pharmacologic...

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Section: Second Generation Forskolin Derivativesmentioning

confidence: 99%

Section: Second Generation Forskolin Derivativesmentioning

confidence: 99%

Plectranthus barbatus: A Review of Phytochemistry, Ethnobotanical Uses and Pharmacology – Part 2

Alasbahi

Melzig²

2010

Planta Med

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“…Studies carried out using one hundred samples belonging to species of Plectranthus and Orthosiphon of the sub family Ocimoideae at Japan also revealed the absence of forskolin in all the samples. Second generation forskolin derivatives viz., 5-6-deoxy-7-deacetyl-7-methyl amino carbon forskolin (HIL568), a potential anti glaucoma agent and 6-(3-dimethylamino propionyl) forskolin hydrochloride (NKH477), a potential cardio tonic agent were developed (Hosono et al,1990). Newer compounds are being identified from the root extracts of P. forskohlii.…”

Section: Phytochemical Properties Of P Forskohliimentioning

confidence: 99%

Review on Pharmacological Effects of <i>Plectranthus f</i><i>orskohlii</i> (Willd) Briq

Lakshmanan

Manikandan

2014

ILNS

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Plectranthus forskohlii (Willd). Briq. (Syn: Coleus forskohlii) is an important indigenous medicinal plant in India. It has been used in traditional Ayurveda medicine for curing various disorders and this is the only source of the diterpenoid forskolin. Forskolin is used for the treatment of eczema, asthma, psoriasis, cardiovascular disorders and hypertension, where decreased intracellular cAMP level is believed to be a major factor in the development of the disease process. A comprehensive account of the morphology, medicinal uses, phytochemistry, pharmacological activities, analytical methods and biotechnological approaches for forskolin production reported are included in view of the many recent findings of importance on this plant.

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“…Water-soluble aminoacylforskolin analogs, for instance, 6-(piperidinoacetyl)-7-deacetylforskolin hydrochloride (HL 706) (Figure 2; 28) and 6-(3-dimethylaminopropionyl)forskolin hydrochloride (NKH 477) (Figure 2; 29) which exhibited the desired biochemical and cardiovascular profile in in vitro and in vivo animal studies, were identified. The considerations which led the group at Nippon Kayaku Ltd., Japan to the selection of NKH 477 for clinical studies, currently in progress in Japan, to evaluate it for the treatment of heart failure have been adequately described (29).…”

Section: Forskolin-derived Compound Hil 568: a Potential Anti-glaucommentioning

confidence: 99%

Rohitukine and Forskolin

Souza¹

1993

ACS Symposium Series

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Rohitukine is the anti-inflammatory principle of Dysoxylum binec tariferum. Forskolin is the unique adenylate cyclase-activating prin ciple of Coleus forskohlii. The cyclic AMP-dependent effects it is known to display are now supplemented by newly discovered cyclic AMP-independent effects. Synthetic and structure-activity relationship studies leading to the development of antiinflammatory, im munomodulatory and anticancer rohitukine analogs, and intraocular pressure-lowering and cardiotonic forskolin analogs are described. A pathway to a forskolin-based antithrombotic phytotherapeutic product is also presented.Our updated findings on the discovery and development of novel human medicinal agents from plants are described herein. These findings represent the current status of a venture that commenced in India over 20 years ago in the 1970s. The objectives, strategies, and results of this sustained mission-oriented venture have been adequately documented (1-5). The venture was sustained in an era when related natural productsoriented efforts were generally at their ebb in the pharmaceutical industry and there was regrettably seen the discontinuation or diminution of ventures worldwide, like that of the Roche Research Institute, Australia, the National Cancer Institute, U.S.A., and the Ciba Research Centre, India. Even in today's era of the 1990s, with the revival of such programs at the National Cancer Institute, U.S.A. and in industry, the realistic picture to be faced is that about the only plant-based novel chemical entities that have emerged as innovative medicines on die market after reserpine are the an ticancer drugs, vincristine, vinblastine, etoposide and taxol. Our venture at Hoechst, aimed at converting plant constituents into novel drugs, owes its sustenance principal ly to our discovery of molecules like rohitukine and forskolin. The new chemical en tities (NCEs) and a potential phytotherapeutic product which have been derived from them are shown in Table I. Rohitukine-Derived HL 275 and HIL 8276Compound HL 275 (designated in the earlier literature as L 86 8275) moved into development as a potential anticancer agent as a consequence of an evolution of events commencing with the isolation of the naturally-occurring chromone 0097-6156/93/0534-0331S06.00A)

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Cardiovascular effects of NKH477, a novel potent water-soluble forskolin derivative

Cited by 15 publications

References 0 publications

Plectranthus barbatus: A Review of Phytochemistry, Ethnobotanical Uses and Pharmacology – Part 2

Plectranthus barbatus: A Review of Phytochemistry, Ethnobotanical Uses and Pharmacology – Part 2

Review on Pharmacological Effects of <i>Plectranthus f</i><i>orskohlii</i> (Willd) Briq

Rohitukine and Forskolin

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