Showing papers on "Growth hormone secretagogue published in 1996"

A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release

Abstract: Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.

Identification of a new G-protein-linked receptor for growth hormone secretagogues

Abstract: The potential application of small molecules in GH therapy has recently become a topic of increasing interest The spiroindoline MK-0677, the benzolactam L-692,429, and the peptides, GHRP-6 and hexarelin, have been shown to possess potent and selective GH-secretory activity in several species including human Moreover, these synthetic GH secretagogues act on a signal transduction pathway distinct from that of GHRH A specific high affinity binding site in porcine and rat anterior pituitary membranes that mediates the activity of these secretagogues has now been identified The binding affinity of these structurally diverse secretagogues is tightly correlated with GH-secretory activity The binding is Mg(2+)-dependent, is inhibited by GTP-gamma-S, and is not displaced by GHRH and somatostatin The receptor is distinct from that for GHRH and has the properties of a new G-protein-coupled receptor It is speculated that these GH secretagogues mimic an unidentified natural hormone that regulates GH secretion i

Growth hormone secretagogues

Abstract: This invention is directed to compounds of formula (I) and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretagogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of formula (I).

2-acylaminopropanamides as growth hormone secretagogues

Abstract: This invention provides a series of substituted propanamides which are useful in the treatment of a physiological condition which may be modulated by an increase in growth hormone. This invention also provides methods for the treatment of such physiological conditions which comprise administering a growth hormone secretagogue as described in the present invention in combination with growth hormone releasing hormone.

Polymorphic forms of a growth hormone secretagogue

Abstract: This invention is concerned with polymorphic forms of the compound N- 1(R)- (1,2-dihydro-1-methanesulfonylspiro 3H-indole-3,4'-piperdin!-1'-yl)carbonyl!-2-(phenylmethyloxy)ethyl!-2-amino-2-methylpropanamide methanesulfonate which is a growth hormone secretagogue that is useful in food animals to promote their growth thereby rendering the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, and to treat medical conditions which are improved by the anabolic effects of growth hormone. The instant polymorphic forms have advantages over the other known forms of N- 1(R)- (1,2-dihydro-1-methanesulfonylspiro 3H-indole-3,4'-piperdin!-1'-yl)carbonyl!-2-(phenylmethyloxy)-ethyl!-2-amino-2-methylpropanamide methanesulfonate in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations. The present invention is also concerned with processes for preparing these polymorphic forms, pharmaceutical formulations comprising these polymorphic forms as active ingredients and the use of the polymorphic form of the compound and their formulations in the treatment of certain disorders.

Process for the preparation of a growth hormone secretagogue

Abstract: The present invention is directed to a novel process for the preparation of the compound N- 1(R)- (1,2-dihydro-1-methanesulfonyl-spiro 3H-indole-3,4'-piperdin!-1'-yl)carbonyl!-2-(phenylmethyl-oxy)ethyl!-2-amino-2-methyl-propanamide, and salts thereof, which has the structure: ##STR1## and which has the ability to stimulate the release of natural or endogenous growth hormone. This compound may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.

2-Acylaminopropanamines as growth hormone secretagogues

Abstract: This invention provides a series of substituted propanamines which are useful in treating a physiological condition which may be modulated by an increase in growth hormone. This invention also provides methods for the treatment of such physiological conditions which comprise administering a growth hormone secretagogue as described in the present invention in combination with growth hormone releasing hormone.

Radiolabeled growth hormone secretagogue

Abstract: The present invention is directed to [35S]-N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof. This [35S] radioligand is useful in identifying and characterizing cellular receptors which play a role in the activity of growth hormone secretagogues. In addition, this [35S] radioligand is useful in assays which test compounds for growth hormone secretagogue activity.

Growth hormone secretagogue receptor family

Abstract: Human, swine and rat growth hormone secretagogue receptors have been isolated, cloned and sequenced. Growth hormone secretagogue receptors are new members of the G-protein family of receptors. The growth hormone secretagogue receptors may be used to screen and identify compounds which bind to the growth hormone secretagogue receptor. Such compounds may be used in the treatment of conditions which occur when there is a shortage of growth hormone, such as observed in growth hormone deficient children, elderly patients with musculoskeletal impairment and recovering from hip fracture and osteoporosis.

Assays for growth hormone secretagogue receptors

Abstract: An assay for the detection of growth hormone secretagogue receptors and growth hormone secretagogue related receptors is described. As these receptors are a member of the G protein coupled receptors, a subunit of the G protein must be present in order for expression to be detected. A similar assay is described where the presence of growth hormone secretagogues are detected.

Pharmacokinetics and disposition of L-692,429. A novel nonpeptidyl growth hormone secretagogue in preclinical species.

Abstract: L-692,429 is a novel nonpeptidyl growth hormone secretagogue that has been demonstrated to stimulate growth hormone secretion in rats, dogs, and humans after intravenous administration. We have examined the pharmacokinetics and disposition of L-692,429 in male Sprague-Dawley rats, beagle dogs, and chimpanzees. Plasma clearance (CLp) of L-692,429 in dogs after intravenous dosing was approximately 18 ml/min/kg and was constant between the doses of 0.1 and 0.9 mg/kg. In rats, CLp after intravenous dosing increased from 3 to 12 ml/min/kg in a dose-dependent manner between 0.1 and 5 mg/kg. In chimpanzees, CLp after an intravenous dose of L-692,429 at 0.5 mg/kg was 5.7 ml/min/kg. In vitro binding of L-692,429 to plasma proteins of dogs, chimpanzees, and humans was approximately 87%, 94%, and 93.5%, respectively, and was independent of concentration. In contrast, plasma binding of L-692,429 was concentration-dependent in rats and decreased from 98.5% to 90.6% between 0.01 and 10 micrograms/ml. Metabolism of L-692,429 was minimal in rats, but moderate in dogs, with the major metabolite being a derivative monohydroxylated at the benzolactam moiety. Thus, the faster clearance of L-692,429 in dogs likely is caused by less extensive plasma protein binding and higher metabolic clearance. The nonlinear pharmacokinetics in rats probably is the result of concentration-dependence in plasma binding. The results of these studies suggest that plasma protein binding plays a major role in determining the values of CLp of L-692,429 among the species. After an intravenous dose of [3H]L-692,429 to rats, liver, kidney, lung, and heart had the highest levels of radioactivity at the early time points, but the gastrointestinal tract had increasing concentrations at later time points. Most of the radioactivity was cleared from all tissues by 24 hr, indicating that L-692,429 did not accumulate in tissues. After intravenous dosing of [3H]L-692,429 to rats and dogs, recoveries of total radioactivity in urine and feces corresponded to approximately 10% and 90%, respectively. Greater than 70% of radioactivity was recovered in bile of rats within 24 hr after intravenous dosing of [3H]L-692,429, indicating that biliary excretion was the primary route of elimination. Based on the combined recoveries of the radioactive dose in bile and urine after an oral dose of L-692,429, oral absorption in rats was approximately 3%. The poor absorption may be the result of the zwitterionic nature of this compound.

Growth Hormone Releasing Peptide—Hexarelin—in Children: Biochemical and Growth Promoting Effects

Abstract: Hexarelin is a synthetic hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe- Lys-NH2) that stimulates the release of pituitary growth hormone both in vitro (1) and in vivo (2). It has proved active also in adult men (3) even when administered by the oral or intranasal route (4, 5). We report forthwith our experience with the acute, short, and longer administration of this peptide to children.

Nonpeptidyl Growth Hormone Secretagogues

Abstract: The availability of recombinant human growth hormone (rhGH) in the mid1980s has fostered a renewed interest in potential clinical applications of growth hormone (GH). In addition to the treatment of GH-deficient children and adults, rhGH may have beneficial effects in the treatment of patients with burns, bone fractures, or Turner’s syndrome, in improving the exercise capacity of elderly individuals, and in reversing the catabolic effects of glucocorticoids, chemotherapy, and AIDS (1–5). While GH is synthesized and stored in the pituitary, its release is regulated by two hypo-thalamic peptides: growth hormone releasing hormone/factor (GHRH/ GHRF) and the inhibitory hormone somatostatin (Fig. 7.1). Most cases of idiopathic GH deficiency are due to a hypothalamic defect and not a pituitary deficiency in GH, and therefore an alternate approach to rhGH treatment of GH-deficient patients would be to administer a GH secretagogue to release endogenous GH (6). For this reason, GRF(l–44)-NH2 and its truncated analogues, e.g., GRF(l–29)-NH2, have been studied over the past decade as an alternate approach in the treatment of GH deficiency (7,8). Although rhGH and GHRF analogues are clinically effective, their high cost and lack of oral bioavailability have restricted their clinical applications.

Evidence for a Central Site and Mechanism of Action of Growth Hormone Releasing Peptide (GHRP-6)

Abstract: Over ten years have elapsed since C.Y. Bowers and colleagues (1) first identified GHRP-6, a potent synthetic hexapeptide that selectively induces growth hormone (GH) secretion from the anterior pituitary gland. During this time, the majority of research has been directed toward understanding the pituitary site and mechanism of action of this compound. More recently, those of us attempting to unravel the neuroendocrine mechanisms controlling pulsatile GH secretion have been forced to consider the possibility that GHRP-6 also acts centrally to control the activity of GH releasing hormone (GHRF) and/or somatostatinergic neurons. By the end of the 1980s, there were various pieces of circumstantial evidence that GHRP-6 may have a direct central action, including the observation that GHRP-6 is considerably more potent when administered in vivo (1) than in vitro (2). Clark and colleagues (3) observed that, in conscious male rats, the spontaneous pulsatile pattern of GH secretion (known to be critically controlled by the GHRF and somatostatin systems) was completely disrupted by an intravenous infusion of GHRP-6. Furthermore, GHRP-6 completely disrupts the normal cyclic refractoriness in the GH response to GHRF (3, 4); since this intermittent responsiveness to GHRF has been attributed to cyclic variations in portal somatostatin concentrations (4), this would imply that GHRP-6 may act centrally to alter the pattern of somatostatin release.

Growth Hormone Secretagogues in Disease States Associated with Altered Growth Hormone Secretion

Abstract: Growth hormone (GH) is necessary for normal linear growth, a fact that conditioned its name and the main focus of research in the last decades (1). Recently, it has become evident that GH exerts other relevant actions over general metabolism, being anabolic, lipolytic, and diabetogenic (2). Furthermore, as a relative GH deficiency is associated with advanced age, this fact has been considered responsible for the deleterious effects of aging on body function and body composition. In this context, understanding the complex mechanisms of GH regulation exerted either by central or peripheral signals is a compelling task.

Combination therapy for osteoporosis consisting of an estrogen agonist/antagonist and a growth hormone secretagogue

Abstract: Pharmaceutical combination compositions including as a first compound estrogen agonists/antagonists and as a second compound sodium fluoride, a parathyroid hormone or growth hormone. The compositions are useful for the treatment of bone disorders including osteoporosis.

Metabolic Regulation of Growth Hormone Secretagogue Gene Expression

Abstract: Growth hormone (GH), secreted from somatotrophs in the anterior pituitary, is a highly regulated hormone that stimulates longitudinal growth and has multiple effects on cellular metabolism. Plasma GH levels vary widely at different times of the day and night, with profound influences of diet, exercise, sleep, and stress in a given individual. GH levels also differ with sex, age, and body habits, providing a challenge to those defining “normal” GH physiology (1–3).