Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist

Ye, Zhixiong; Guo, Liangqin; Barakat, Khaled; Pollard, Patrick G.; Palucki, Brenda L.; Sebhat, Iyassu K.; Bakshi, Raman K.; Tang, Rui; Kalyani, Rubana N.; Vongs, Aurawan; Chen, Airu S.; Chen, Howard Y.; Rosenblum, Charles; MacNeil, Tanya; Weinberg, David H.; Peng, Qianping; Tamvakopoulos, Constantin; Miller, Randy R.; Stearns, Ralph A.; Cashen, Doreen E.; Martin, William J.; Metzger, Joseph M.; Strack, Alison M.; MacIntyre, D. Euan; Ploeg, Lex H.T. Van der; Patchett, Arthur A.; Wyvratt, Matthew J.; Nargund, Ravi P.

doi:10.1016/j.bmcl.2005.05.109

Cited by 37 publications

(10 citation statements)

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“…On the basis of this mechanistic information, various piperazine analogs with pendant alkyl groups (Scheme ) were prepared and tested for protein covalent binding with radiolabeled versions of the parent compounds . Several alkylpiperazines 129 – 132 retained melanocortin receptor agonist activity and demonstrated ∼10-fold reduction in covalent binding (relative to 122 ). , In particular, a bridged isoquinuclidine derivative 133 , which exhibited considerably less covalent binding (∼26 pmol equivalent/mg of microsomal protein) to rat and human microsomal protein when compared with 122 , was also orally active as a melanocortin receptor agonist …”

Section: Resolution Of Reactive Metabolite Liabilities Of Cyclic Aminesmentioning

confidence: 99%

Designing around Structural Alerts in Drug Discovery

Kalgutkar

2019

J. Med. Chem.

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Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds.Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure−metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/ reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.

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Section: Resolution Of Reactive Metabolite Liabilities Of Cyclic Aminesmentioning

confidence: 99%

Designing around Structural Alerts in Drug Discovery

Kalgutkar

2019

J. Med. Chem.

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“…Some Mc4 receptor agonists have been tested in preclinical and clinical studies. A melanocortin 4 receptor agonist, 3 RY764, reduced food intake and augmented erectile activity in rodents [62]. MK-0493, another potent and selective agonist of Mc4 receptor, was associated with statistically insignificant weight reductions in a clinical trial[63].…”

Section: Novel Targets and Drug Candidatesmentioning

confidence: 99%

Obesity Pharmacotherapy: Current Perspectives and Future Directions

Misra

2013

CCR

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Abstract:The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis

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“…1F) [41][42] MB-243 (Fig. 1H) [44] developed at Merck & Company and an isoquinoline based compound developed at Trega Biosciences (TRG-2411#203; [45][46]; Fig. 1H) [44] developed at Merck & Company and an isoquinoline based compound developed at Trega Biosciences (TRG-2411#203; [45][46]; Fig.…”

Section: Melanocortins and Sexual Functionmentioning

confidence: 99%

“…1H) [44] developed at Merck & Company and an isoquinoline based compound developed at Trega Biosciences (TRG-2411#203; [45][46]; Fig. However, it has been reported to augment magnitude and duration of electrically stimulated erectile activity upon IV administration of 1 mg/kg dose in mice [44]. THIQ (MC-4R Ki 2nM) is an MC-4R selective agonist that has been studied in detail in rat models.…”

Section: Melanocortins and Sexual Functionmentioning

confidence: 99%

“…Using this model, 50 g/kg of IN bremelanotide caused 100% of treated rats to have at least one erectile event and significantly increased the mean number of spontaneous erections during the 30-minute observation period following treatment [47]. A third model for the study of MCR agonists involves measurement of interacovernosal pressure by telemetry in either anesthetized animals following electrical stimulation and drug treatment [44] or with a radiotelemetric pressure transducer implanted in the corpus cavernosum in a freely moving rat following drug treatment [48]. Investigators at Merck [42] have used the excopula rat model for testing MCR agonists where reflexive erections are induced by the tactile stimulus of retracting the sheath surrounding the penis.…”

Section: Male Sexual Dysfunctionmentioning

confidence: 99%

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Melanocortins in the Treatment of Male and Female Sexual Dysfunction

Hallam

Spana

Earle

et al. 2007

CTMC

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Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.

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Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist

Cited by 37 publications

References 50 publications

Designing around Structural Alerts in Drug Discovery

Designing around Structural Alerts in Drug Discovery

Obesity Pharmacotherapy: Current Perspectives and Future Directions

Melanocortins in the Treatment of Male and Female Sexual Dysfunction

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