SCH-497079: A Comprehensive Review of its Development and Discontinuation

1. Introduction to SCH-497079

1.1. Overview and Identification

SCH-497079 is identified as an investigational small molecule drug.[1] It is also referred to by the synonym SCH 497079.[1] The primary pharmacological target of SCH-497079 is the Histamine H3 receptor (H3R), for which it acts as an antagonist.[1] This initial identification frames SCH-497079 as a compound designed to modulate the histaminergic system, with potential therapeutic implications stemming from the diverse roles of H3 receptors in the central nervous system and periphery.

1.2. Originator and Developer

The development of SCH-497079 was primarily attributed to Merck Sharp & Dohme Corp. (also referred to as Merck & Co.).[1] Schering-Plough is also significantly associated with its development, particularly noted in the context of its H3 receptor antagonist properties and clinical trials for obesity.[3] The timeline of SCH-497079's development coincides with the merger of Merck & Co. and Schering-Plough Corp., which was announced in March 2009 and completed later that year.[5] This corporate integration is a pertinent factor, as such events often lead to reviews and reprioritization of research and development pipelines. The discontinuation of SCH-497079 during its Phase 2 clinical development could have been influenced not only by scientific findings regarding its efficacy and safety but also by strategic decisions made in the wake of this major pharmaceutical merger. Other entities listed as inactive organizations in its development include Merck GmbH and Merck Sharp & Dohme LLC.[1]

1.3. Drug Class

SCH-497079 is categorized as an obesity therapy based on its intended application.[2] More broadly, its therapeutic focus falls within endocrinology and metabolic diseases.[1] Its mechanism of action as a Histamine H3 receptor antagonist further defines its pharmacological class.[1] This classification underscores the primary therapeutic ambition for SCH-497079, directly linking its molecular mechanism to the physiological systems it was intended to modulate.

The early developmental landscape of SCH-497079, involving major pharmaceutical entities like Merck and Schering-Plough, points to the significant interest and resources once allocated to H3 receptor antagonists for metabolic disorders. The subsequent merger of these companies forms a critical backdrop to the drug's developmental timeline and eventual discontinuation, suggesting that strategic R&D pipeline alignments post-merger may have played a role alongside emerging clinical data.

2. Pharmacological Profile

2.1. Mechanism of Action

SCH-497079 functions as a Histamine H3 (H3) receptor antagonist.[1] Some sources further specify its action as that of an H3 receptor antagonist/inverse agonist.[6] The H3 receptor is predominantly a presynaptic G-protein coupled receptor that acts as an autoreceptor on histaminergic neurons, inhibiting the synthesis and release of histamine. Additionally, H3 receptors function as heteroreceptors on non-histaminergic neurons, modulating the release of other crucial neurotransmitters such as norepinephrine, dopamine, serotonin, and acetylcholine.[4]

By antagonizing or acting as an inverse agonist at H3 receptors, SCH-497079 was expected to disinhibit these presynaptic receptors, thereby increasing the release of histamine and potentially other neurotransmitters in the brain and periphery. This increased neurochemical activity was hypothesized to influence a variety of physiological processes, including the regulation of food intake, energy expenditure, wakefulness, and cognitive functions.[4] The distinction between a simple antagonist (which blocks the receptor) and an inverse agonist (which reduces constitutive receptor activity) can have nuanced implications for the overall pharmacological effect, though the practical difference for SCH-497079's development is not explicitly detailed in the available information.

2.2. Intended Therapeutic Areas and Indications

The pharmacological properties of SCH-497079 led to its investigation across a few therapeutic areas:

• Obesity / Weight Gain: This was a primary focus for SCH-497079, with clinical development reaching Phase 2.[1] The rationale stemmed from preclinical evidence suggesting that H3R antagonists could reduce food intake, decrease body weight, and improve metabolic parameters in animal models of obesity.[4] The histaminergic system is known to play a role in the central regulation of appetite and energy homeostasis.
• Diabetes Mellitus, Type 2: SCH-497079 was investigated for Type 2 Diabetes up to Phase 1.[1] Preclinical studies had suggested that H3R antagonists might also favorably impact glucose metabolism by reducing blood glucose levels.[7]
• Seasonal Allergic Rhinitis: A Phase 2 clinical trial (EUCTR2004-001883-39-AT) explored the use of SCH-497079 in co-administration with desloratadine (an H1 receptor antagonist) for the treatment of nasal congestion associated with seasonal allergic rhinitis.[1] This indication leveraged the well-established role of histamine in allergic inflammation.

The pursuit of SCH-497079 for obesity and type 2 diabetes was part of a broader therapeutic strategy within the pharmaceutical industry to target the H3 receptor for metabolic conditions. However, this approach has historically faced significant hurdles. The failure of SCH-497079 to demonstrate sufficient efficacy or an acceptable safety profile for these indications contributes to a larger pattern of difficulty in translating the preclinical promise of H3R antagonists into clinically successful treatments for metabolic disorders.[4] The complex pharmacology of the H3 receptor, with its widespread distribution and influence on multiple neurotransmitter systems, may inherently lead to a narrow therapeutic window or a range of off-target effects when systemically modulated for conditions like obesity. This complexity could make it challenging to achieve the desired therapeutic benefit without inducing unacceptable side effects. The exploration of SCH-497079 for seasonal allergic rhinitis, a more localized and directly histamine-mediated condition, might have represented an attempt to find a therapeutic niche where the risk-benefit profile could be more favorable, especially in combination with an established antihistamine.

3. Clinical Development Program

3.1. Overview of Clinical Trials

The clinical development of SCH-497079 involved several studies, primarily targeting obesity and metabolic parameters, with an additional trial investigating its potential in seasonal allergic rhinitis. Despite these efforts, the drug did not progress beyond Phase 2 clinical trials before its development was discontinued.[1]

3.2. Trial NCT00642993 (Obesity/Weight Gain)

This Phase 2 study, titled "A Multicenter, Randomized, Parallel-Group, Placebo-Controlled, Efficacy and Safety Trial to Evaluate the Effect of SCH 497079 on Weight in Obese and Overweight Subjects," was a pivotal trial for SCH-497079's primary indication.[1] The trial was completed and involved 401 subjects.[1] While the sponsor is not explicitly named in all database entries, it was likely Schering-Plough, which was later acquired by Merck.[1]

The primary objective was to assess the efficacy and safety of SCH 497079 in promoting weight loss in obese and overweight individuals. Specific outcome data from this trial are not clearly presented in the available information; some database entries show coded or obscured results (e.g., "ufkhstoeeu(ncrktixjnk) = gevjvfxjoo fpznyiffsd (cdkciuqgdh, 0.19)" for SCH 497079) dated October 27, 2016, which are not interpretable without further context.[1] However, the broader scientific literature suggests that this trial, and others involving H3R antagonists for obesity, did not yield sufficiently positive results. Publications frequently cite NCT00642993 in discussions about the limited success or discontinuation of H3R antagonists for obesity, often due to low efficacy.[4]

3.3. Trial NCT00673465 (Metabolic Parameters)

This Phase 1 study was a "Randomized, Placebo-controlled, Three-Way Crossover Study to Evaluate the Effect of SCH 497079 on Metabolic Parameters and to Determine the Influence of Race/Ethnic Origin on Therapeutic Response".[1] It was also completed and sponsored by Schering-Plough/Merck. The trial aimed to assess the drug's impact on various metabolic markers and to explore potential differences in response based on race or ethnic origin. Specific efficacy or safety outcomes from this particular Phase 1 trial are not detailed in the provided materials, beyond its completion and its citation in literature discussing H3R antagonists.[7] This study would have provided crucial early data on safety, tolerability, pharmacokinetics, and pharmacodynamics, informing the progression to Phase 2 trials for obesity and type 2 diabetes.

3.4. Trial EUCTR2004-001883-39-AT (Seasonal Allergic Rhinitis)

This Phase 2 trial, conducted in Austria (AT), was titled "Study to Evaluate the Effect of the Coadministration of SCH 497079 (a Histamine 3 [H3] Receptor Antagonist) Plus Desloratadine on Nasal Congestion in Subjects With Seasonal Allergic Rhinitis Who Have Been Exposed to Pollen in the Vienna Challenge Chamber (VCC) - H3 POC".[1] The global completion date for this trial was January 14, 2005, with results published on the EudraCT database on August 14, 2016.[9] Some database entries list this trial as "not yet recruiting," which appears to be outdated information given the completion and results publication dates.[1] The sponsor is not explicitly stated in the provided snippets for this specific EU trial. The objective was to assess the efficacy of SCH 497079 when combined with desloratadine in alleviating nasal congestion due to seasonal allergies. A redacted synopsis of the results is available, but detailed efficacy or safety data are not present in the snippets.[9]

3.5. Summary of Clinical Trials for SCH-497079

The following table summarizes the key clinical trials conducted for SCH-497079 based on the available information:

Trial Identifier	Phase	Indication(s)	Status	Sponsor (Likely)	Key Findings/Reason for Discontinuation (based on snippets)
NCT00642993	Phase 2	Obesity, Weight Gain	Completed	Schering-Plough/Merck	Results unclear from snippets; literature suggests low efficacy leading to discontinuation.1
NCT00673465	Phase 1	Metabolic Parameters, Type 2 Diabetes	Completed	Schering-Plough/Merck	Completed; specific outcomes not detailed in snippets.1
EUCTR2004-001883-39-AT	Phase 2	Seasonal Allergic Rhinitis (with Desloratadine)	Completed	Not Specified	Completed in 2005; redacted synopsis available; specific outcomes not detailed in snippets.9

The clinical development path of SCH-497079 was comparatively restricted, failing to advance beyond Phase 2 for its principal indications of obesity and related metabolic disorders. This limited progression suggests that the early-phase trials did not generate sufficiently compelling evidence of efficacy or an acceptable safety margin to justify moving into larger, more expensive Phase 3 studies. There is a notable absence of detailed, publicly accessible positive results from these key trials within the provided information. Instead, the available data and literature references frequently point towards incomplete data disclosure, unpublished results, or ultimately, unfavorable outcomes that led to the drug's discontinuation.[4] This pattern strongly implies that the trials did not meet their primary objectives or revealed issues that precluded further development. The challenges in demonstrating clear efficacy and safety in these early-phase trials were likely primary contributors to the decision to halt the development of SCH-497079. This situation is not uncommon in pharmaceutical R&D, reflecting the high attrition rates for investigational drugs, particularly those with novel mechanisms or targeting complex, multifactorial diseases like obesity. The exploration of an alternative indication like allergic rhinitis might have been a strategic consideration following less than convincing initial data in the metabolic sphere.

4. Reported Efficacy and Safety

4.1. Efficacy

The clinical efficacy of SCH-497079, based on the available information, appears to have been insufficient to support continued development for its primary targeted indications.

• Obesity/Weight Gain: Clinical trial NCT00642993 was specifically designed to evaluate SCH 497079's effect on weight in obese and overweight subjects.[1] However, the outcomes were not favorable. Scientific literature indicates that these trials "did not meet up he expectations," and results were either not published or the drug was discontinued due to "low efficacy".[4] The coded results presented in some database entries for NCT00642993 do not offer clear evidence of clinical benefit.[1] This lack of demonstrated efficacy was a critical factor in the decision to halt development for obesity.
• Metabolic Parameters (including Type 2 Diabetes): While preclinical studies suggested potential benefits of H3R antagonists on blood glucose levels [7], these did not translate into successful clinical outcomes for SCH-497079. The drug was investigated in Phase 1 (NCT00673465) for its effects on metabolic parameters, but development for Type 2 Diabetes did not proceed beyond this stage, indicating a lack of promising signals.[1] No specific efficacy data from NCT00673465 are available in the snippets.
• Seasonal Allergic Rhinitis: The Phase 2 trial EUCTR2004-001883-39-AT assessed SCH 497079 in combination with desloratadine for nasal congestion.[1] Although the trial was completed in 2005 and a redacted synopsis of the results is available, specific efficacy outcomes are not detailed in the provided information.[9] The lack of further development for this indication suggests that the combination did not offer a significant enough advantage to pursue.

The overarching theme from the available information is a failure to demonstrate clinically meaningful efficacy, particularly for the primary indication of obesity, which was a significant hurdle for SCH-497079.

4.2. Safety and Tolerability

Safety and tolerability concerns also played a role in the discontinuation of SCH-497079. The development program was halted, with "side effects" cited as a contributing reason.[12] These citations refer to a review by Colon-Gonzalez et al. (2013), which reportedly mentioned the discontinuation due to side effects.

Unfortunately, the specific nature, frequency, or severity of these adverse events experienced in the SCH-497079 clinical trials are not detailed in the provided snippets. The full text of the critical reference by Colon-Gonzalez et al. (2013), which might contain such details, was not fully accessible within the research materials.[13] Without these specifics, a detailed assessment of the safety profile is not possible, but the general mention of "side effects" as a reason for discontinuation points towards an unfavorable risk-benefit assessment.

The primary challenge for SCH-497079 appears to have been a confluence of insufficient efficacy and an undesirable safety profile, particularly for its main intended uses in obesity and metabolic disorders. A drug might find a therapeutic niche if it shows modest efficacy but has an excellent safety profile, or vice-versa (for severe conditions). However, failing to meet adequate thresholds for both efficacy and safety makes further development untenable, especially for chronic conditions requiring long-term treatment. The complex pharmacology of H3 receptors, which are widely distributed and modulate various neurotransmitter systems [4], may inherently predispose H3R antagonists to a complex side effect profile when administered systemically. This could explain the general waning of pharmaceutical industry interest in H3R antagonism as a viable anti-obesity strategy.[4]

5. Discontinuation of Development

5.1. Stated Reasons for Discontinuation

The development of SCH-497079 was ultimately terminated. The available information points to two primary reasons for this decision:

• Low Efficacy: Multiple sources indicate that SCH-497079 failed to demonstrate sufficient clinical efficacy. A publication by Leurs et al. (2011) explicitly states that SCH-497079 was not developed further due to "low efficacy".[10] Another publication notes that clinical trials for H3R antagonists in obesity, including SCH-497079, "did not meet up he expectations".[4] This suggests that the drug did not achieve the predefined endpoints for weight loss or metabolic improvement in its clinical trials.
• Side Effects: Adverse effects also contributed to the discontinuation. Kotanska et al. (2021), citing Colon-Gonzalez et al. (2013), state that SCH-497079 was "removed from further studies" due to "side effects".[12] This indicates that the drug's tolerability profile was not acceptable for continued development, likely outweighing any potential benefits observed.

While some older database entries from around 2013 indicated the "current status not known" for SCH-497079 in Phase 2 obesity trials by Schering-Plough [3], more recent and comprehensive reviews confirm its discontinuation.[1] The combination of insufficient therapeutic benefit and safety concerns provides a clear rationale for halting the drug's progression.

5.2. Development Stage at Discontinuation

SCH-497079 reached Phase 2 of clinical development for its primary indications of obesity and for seasonal allergic rhinitis. For Type 2 Diabetes, it was investigated up to Phase 1.[1] The decision to discontinue was made at the Phase 2 stage.[1] Discontinuation at this phase is a common occurrence in the pharmaceutical industry, often resulting from a failure to confirm initial efficacy signals seen in Phase 1 or the emergence of safety concerns as the drug is tested in a larger and more diverse patient population.

The discontinuation of SCH-497079 due to both inadequate efficacy and an unfavorable side effect profile suggests a fundamental issue with the drug's therapeutic index for the conditions it was intended to treat. A therapeutic index reflects the balance between a drug's desired effects and its adverse effects. If a drug is not effective enough, or if its side effects are too severe or frequent relative to its benefits, its therapeutic index is considered poor, making further development unviable. This was evidently the case for SCH-497079 in the context of chronic conditions like obesity and type 2 diabetes, where long-term administration would be necessary.

The timeline of information release regarding SCH-497079's trial outcomes and discontinuation also illustrates a common pattern in pharmaceutical research. Initial database entries might simply mark a trial as "completed" or its status as "unknown" for a period.[1] Formal announcements of discontinuation and the underlying reasons often emerge later, through scientific publications, reviews, or updated drug development pipelines.[4] This lag can be attributed to the time required for full data analysis, internal review processes, and decisions regarding publication strategies. The failure of SCH-497079 likely contributed to the broader reassessment within the pharmaceutical industry regarding the viability of H3 receptor antagonism as a therapeutic strategy for obesity.[4] This highlights how outcomes from individual drug programs can influence wider research trends and investment in specific biological targets.

6. Chemical Information, Publications, and Patents

6.1. Chemical Information

SCH-497079 is characterized as a small molecule drug.[1] Its common synonym is SCH 497079.[1] Detailed chemical information such as its specific chemical structure, CAS (Chemical Abstracts Service) registry number, or SMILES (Simplified Molecular Input Line Entry System) notation is not directly provided in the accessible portions of the research snippets. While databases like PubChem [18], ChEMBL [7], and various patent databases [22] are typical repositories for such data, the query results within the provided material either do not contain this specific information for SCH-497079 or the relevant database entries were inaccessible or lacked detail.[33] The absence of this precise chemical data within the provided scope limits a full physicochemical characterization of the compound.

6.2. Scientific Publications

SCH-497079 has been mentioned in a number of scientific publications, predominantly within reviews discussing obesity pharmacotherapy or the broader class of H3 receptor antagonists.

Key mentions include:

• Kotanska et al. (2021, Int J Mol Sci) noted that SCH-497079's Phase II trials were completed, but the compound was subsequently removed from further studies due to side effects, referencing Colon-Gonzalez et al. (2013).[12]
• Leurs et al. (2011, Trends Pharmacol Sci), cited as reference in several snippets [10] and available as [11], stated that SCH-497079 was not developed further owing to low efficacy.
• Ashek et al. (2019, Journal of Medicinal Chemistry) mentioned SCH-497079 alongside HPP-404 as H3R antagonists that had been evaluated in clinical trials for obesity and diabetes.[5]
• A 2013 publication on ResearchGate concerning bicyclic and tricyclic heterocycle derivatives as H3R antagonists observed that clinical trials exploring H3R as an antiobesity target, including those for SCH-497079, "did not meet up he expectations and were interrupted or results were not published".[4]

Notably, primary research articles detailing the specific efficacy and safety results from the pivotal clinical trials of SCH-497079 (NCT00642993, NCT00673465) are not directly provided or summarized in the available snippets. The literature tends to discuss SCH-497079 retrospectively, focusing on its discontinuation and the general challenges faced by H3R antagonists, rather than presenting original positive findings.

6.3. Patents

Information regarding patents specifically covering the composition of matter, synthesis, or use of SCH-497079 is limited within the provided snippets. Databases like Patsnap Synapse indicate the association of "100 Patents (Medical) associated with SCH-497079" but require privileged access to view the details.[1] Direct searches of patent databases using the available snippets did not yield accessible, specific patent numbers, inventor details, or claims directly linked to SCH-497079's unique chemical entity or manufacturing processes.[6]

There appears to be a notable gap in publicly accessible, detailed primary data for SCH-497079 from the provided research materials. This is particularly true for its definitive chemical structure and the comprehensive results of its clinical trials. While specialized databases like Patsnap Synapse suggest the existence of such information (e.g., clinical results, patents), this data is often behind paywalls or requires subscriptions, limiting its availability for general review.[1] The published literature that is accessible tends to refer to SCH-497079's discontinuation or discusses it within the broader context of its drug class, rather than presenting in-depth primary data from its development program. This lack of readily available, transparent information makes a complete, independent assessment of SCH-497079's development and the precise reasons for its failure challenging based solely on the provided materials. This situation is not unique to SCH-497079 and reflects a broader issue where detailed data from discontinued investigational drug programs are not always widely disseminated, potentially hindering collective learning within the scientific community from development failures. While proprietary interests are understandable, greater transparency regarding specific efficacy shortfalls or detailed adverse event profiles could offer valuable lessons for future drug discovery and development efforts targeting similar mechanisms or therapeutic areas.

7. Conclusion and Implications

7.1. Summary of SCH-497079's Development Trajectory

SCH-497079 was a small molecule Histamine H3 receptor antagonist developed by Merck Sharp & Dohme Corp. and Schering-Plough. It was primarily investigated for the treatment of obesity and type 2 diabetes, with clinical trials reaching Phase 2 and Phase 1 for these respective indications. An additional Phase 2 trial explored its use in seasonal allergic rhinitis when co-administered with desloratadine. Despite the initial preclinical rationale based on the role of H3 receptors in modulating histamine and other neurotransmitter release involved in appetite and metabolism, the clinical development program for SCH-497079 was ultimately discontinued. The primary reasons cited for this discontinuation were a combination of low clinical efficacy and the emergence of undesirable side effects.[4] While specific details of the clinical trial results and the nature of the adverse events are not fully transparent in the publicly available information from the provided sources, the consensus points to an unfavorable risk-benefit profile that did not support further development.

7.2. Potential Lessons Learned and Broader Implications

The development and subsequent discontinuation of SCH-497079 offer several insights into the complexities of pharmaceutical research and development, particularly when targeting receptors with broad physiological roles for multifactorial diseases. The H3 receptor, with its extensive distribution and modulatory effects on numerous neurotransmitter systems [4], presents a challenging target. While antagonism of this receptor showed promise in preclinical models for metabolic disorders, translating these findings into safe and effective human therapies proved difficult. This underscores a persistent challenge in drug development: the predictive limitations of preclinical models for complex human diseases and drug responses.

The experience with SCH-497079 likely contributed to a broader reassessment within the pharmaceutical industry regarding the viability of H3 receptor antagonists as a therapeutic strategy for obesity.[4] The failure to achieve a favorable therapeutic index—sufficient efficacy coupled with acceptable tolerability—is a common pitfall. For H3R antagonists, the diverse physiological roles mediated by the receptor may make it inherently difficult to isolate desired therapeutic effects (e.g., appetite suppression) without concurrently triggering unwanted effects elsewhere in the body, leading to a complex side effect profile.

Future endeavors targeting the H3 receptor might necessitate more sophisticated approaches. This could involve the development of compounds with greater selectivity for specific H3 receptor subtypes (if functionally distinct subtypes relevant to therapeutic effects are identified), a better understanding of tissue-specific receptor function and downstream signaling pathways, or the exploration of indications where the risk-benefit assessment might be different (e.g., certain neurological or psychiatric disorders where H3R modulation has also been proposed [6]). Additionally, novel drug delivery systems aimed at optimizing target engagement while minimizing systemic exposure could potentially improve the therapeutic window for this class of compounds. The story of SCH-497079 serves as a reminder of the high attrition rates in drug development and the importance of rigorous evaluation at each phase to ensure that only compounds with a clear positive benefit-risk balance proceed to market.

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