NK1R antagonists(Neurokinin 1 receptor antagonists), NK2R antagonists(Neurokinin 2 receptor antagonists), NK3 antagonists(Neurokinin 3 receptor antagonists)

Therapeutic Areas

Immune System DiseasesRespiratory Diseases

Active Indication

AsthmaCoughPulmonary Disease, Chronic Obstructive

Inactive Indication-

Originator Organization

Schering-Plough Corp.

Active Organization

Schering-Plough Corp.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC33H41Cl4N5O4

InChIKeyUITMLIVWRRGLLR-SUFYPKAWSA-N

CAS Registry226915-43-1

100 Clinical Results associated with SCH-206272

100 Translational Medicine associated with SCH-206272

100 Patents (Medical) associated with SCH-206272

Literatures (Medical) associated with SCH-206272

01 Dec 2010·Birth Defects Research Part B: Developmental and Reproductive Toxicology

Effects of an antagonist of neurokinin receptors 1, 2 and 3 on reproductive hormones in male beagle dogs

Article

Author: Michael W. Leach ; Barry S. McIntyre ; Fernand LaBrie ; Brian P. Enright ; Patricia E. Losco ; Georges Pelletier

AbstractBACKGROUND: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels. METHODS: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH. RESULTS: Intact male dogs exhibited SCH 206272‐related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272‐related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post‐dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post‐dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH‐containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post‐dosing. CONCLUSIONS: SCH 206272‐dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272‐related reproductive tract findings are the result of alterations in hypothalamic–pituitary–gonadal function. However, a direct effect on the testes cannot be definitively ruled out. Birth Defects Res (Part B) 89:517–525, 2010. © 2010 Wiley‐Liss, Inc.

01 Feb 2007·Toxicologic PathologyQ4 · MEDICINE

Administration of an Antagonist of Neurokinin Receptors 1, 2, and 3 Results in Reproductive Tract Changes in Beagle Dogs, but Not Rats

Q4 · MEDICINE

Article

Author: Reyderman, Larisa ; Schmahai, Theodore J. ; Losco, Patricia E. ; Davis, Preston ; Kakkar, Tarundeep ; Lynch, Mary Ellen ; Leach, Michael W. ; Nomier, Amin ; Sinha, Dineshwar

SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33–86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.

01 Aug 2003·Current Topics in Medicinal ChemistryQ4 · MEDICINE

Development and Potential Utility of Dual and Triple NK Receptor Antagonists

Q4 · MEDICINE

Review

Author: Rizzo, Charles A. ; Shih, Neng-Yang ; Anthes, John C. ; Reichard, Greg A. ; Ng, Kwokei J. ; Corboz, Michel R. ; Hey, John A. ; Chapman, Richard W.

The mammalian tachykinin (TK) peptides and their three neurokinin (NK) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests pathophysiological relevance for TKs in various diseases including asthma, emesis and depression. The promiscuous TK-NK receptor interactions and incompletely overlapping functions mediated by each NK receptor may indicate added therapeutic benefit of using multiple NK receptor blockade. Consequently, there has been substantial pharmaceutical effort in projects to develop nonpeptide dual and triple NK receptor antagonists. This review identifies the chemical and biological approach used to develop a TK antagonist active at the three NK receptors. Clinical activity has been observed using single and/or dual NK receptor antagonists in asthma, depression/anxiety and, most notably, emesis trials but no compound with mono or multiple NK receptor antagonist activities has cleared all the development and regulatory hurdles to commercialization. Current experience indicates that potent dual and triple NK receptor-selective antagonists possessing appropriate affinity and pharmacokinetic properties can be developed. As an example, the biological and pharmacokinetic profiles of a new representative of this class of agent, SCH 206272, is detailed in the present review. Whether such agents will fulfill researchers' expectations must await further clinical trials.

100 Deals associated with SCH-206272

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Preclinical	US	Schering-Plough Corp.	-
Cough	Preclinical	US	Schering-Plough Corp.	-
Pulmonary Disease, Chronic Obstructive	Preclinical	US	Schering-Plough Corp.	-

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