WO2023242810A1 - Antagonistes de mchr1 pour le traitement du syndrome de prader-willi - Google Patents

Antagonistes de mchr1 pour le traitement du syndrome de prader-willi Download PDF

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WO2023242810A1
WO2023242810A1 PCT/IB2023/056245 IB2023056245W WO2023242810A1 WO 2023242810 A1 WO2023242810 A1 WO 2023242810A1 IB 2023056245 W IB2023056245 W IB 2023056245W WO 2023242810 A1 WO2023242810 A1 WO 2023242810A1
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use according
mchr1 antagonist
pharmaceutically acceptable
mchr1
acceptable salt
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Márk OLÁH
András BOROS
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Richter Gedeon Nyrt.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4

Definitions

  • the present invention relates to uses of a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the treatment of Prader-Willi Syndrome (PWS), for improving, alleviating or delaying progression of one or more symptoms of PWS, such as hyperphagia, for maintaining or reducing body weight, or for reducing food intake in a patient afflicted with PWS.
  • MCHR1 melanin-concentrating hormone receptor 1
  • PWS Prader-Willi Syndrome
  • PWS Prader-Willi syndrome
  • PWS is a rare complex neurodevelopmental genetic disorder - resulting from absence of expression of imprinted genes in the paternally derived region of the chromosome 15ql l.2-ql3.
  • PWS is the most common syndromic cause of life-threatening obesity with an estimated incidence of 1/10 000 to 1/25 000 live births, occurring equally in both males and females, and across all ethnicities.
  • the course and early natural history of PWS can be divided into two distinct clinical stages.
  • the first stage occurs during the neonatal and early infancy periods and is characterized by varying degrees of hypotonia, a weak cry, a narrow forehead, developmental delay, temperature instability, a poor suck reflex, sticky saliva, feeding difficulties sometimes requiring gastrostomy or stomach tube placement, hypogonadism, and underdevelopment of the sex organs. Failure-to-thrive is noted during this first stage.
  • the hypotonia is thought to be central in origin, non-progressive, and on the average begins to improve between 8 and 11 months of age.
  • the delay in achieving motor milestones appears to relate more to psychomotor development than to excessive obesity.
  • the second stage usually begins around 2 years of age and is characterized by continued developmental delay or psychomotor retardation and onset of hyperphagia leading to obesity.
  • Other features noted during the second stage may include speech articulation problems, foraging for food, rumination, unmotivated sleepiness (found in greater than 50% of subjects), physical inactivity, decreased pain sensitivity, skin picking and other forms of self-injurious behavior, prolonged periods of hypothermia, strabismus, hypopigmentation, scoliosis, obstructive sleep apnea, and abnormal i oral pathology.
  • infants and toddlers are usually easy-going and affectionate, but in about one half of PWS subject personality problems develop between 3 and 5 years of age.
  • Temper tantrums, depression, stubbornness, obsessive compulsivity, and sudden acts of violence of varying degrees may be observed during this stage. These behavioral changes may be initiated by withholding of food but may occur with little provocation during adolescence or young adulthood. Poor peer interactions, immaturity, and inappropriate social behavior may also occur during this time (Butler, Lee, Whitman, Eds. Springer, Management of Prader-Willi Syndrome, Third Edition, 2006).
  • PWS Many clinical features in PWS may be subtle or non-specific while other features are more characteristic for the disorder.
  • the primary features of PWS include infantile hypotonia, feeding difficulties, mental deficiency, hypogonadism, behavior problems (temper tantrums, stubbornness, obsessive-compulsive disorder), hyperphagia and early childhood onset of obesity, small hands and feet, endocrine disturbances including recently identified growth hormone deficiency, and a characteristic facial appearance.
  • Hyperphagia the key behavioral symptom in PWS has remarkable impact on patient and caregiver well-being that extends far beyond the effect of weight gain alone. Management of hyperphagia is ranked as the highest priority among priorities for PWS treatment goals among caregivers. Caregivers would accept significant risk in exchange for improvement of hyperphagic behavior (Tsai et al., MDM Policy Pract. 2021 Jul-Dec; 6(2): 23814683211039457). Much of the morbidity and mortality in PWS is related to the clinical impact of obesity consequent upon the hyperphagia. Life expectancy for people with PWS is reduced with estimates of a 3% mortality rate per year for those with the syndrome. The behavior of hyperphagia itself, independent of obesity, is commonly associated with choking, gastric rupture, and/or respiratory illness (Bellis et al., E r J Med Genet. 2022 Jan; 65(1): 104379).
  • hyperphagia is a core symptom of PWS patients from about 4 years of age till early adulthood (Miller et al., Am J Med Genet A. 2011 May; 155 A (5): 1040- 9) and is responsible for enormous burden of the entire family or community (Kayadjanian et al., PLoS ONE 16(3): e0248739).
  • Zafgen s phase 3 trial of the methionine aminopeptidase 2 Inhibitor ZGN-440 (beloranib) in overweight or obese subjects with PWS was halted and the development was terminated due to high risk of thrombotic events resulting death during the clinical trial (McCandless et al., Diabetes Obes Metab. 2017 Dec;19(12):1751-1761).
  • ghrelin-O-acyltransferase (GOAT) inhibitor GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers (Miler et al., J Clin Endocrinol Metab, 2022 May 17;107(6): e2373-e2380).
  • Rhythm Pharma completed a Phase 2 proof of concept, double -blind, placebo- controlled, randomized clinical trial in PWS with the melanocortin-4 receptor agonist setmelanotide (study RM-493-010), which enrolled 40 patients with PWS.
  • the results of the trial showed modest effects on hyperphagia, which did not approach statistical significance, and no effect on weight (Rhythm Pharmaceuticals Form S-l https ://www . sec .gov/Archives/edgar/data/ 1649904/000104746917006046/a2233203zs- la.htm).
  • Carbetocin is an oxytocin analog with improved specificity for oxytocin receptors.
  • administration of carbetocin to individuals with PWS improved hyperphagia and some other behavioral measures. Demonstration of dose-response relationship was failed in Phase 3 and FDA rejected the new drug application (https://www.levotx.com/news/levo- receives-crl-for-intranasal-carbetocin/).
  • 0X1 orexin receptor antagonists are of interest to treat, relevant for PWS, personality disorders, eating disorders, or anxiety-related disorders.
  • known dual 0X1/0 X2 receptor antagonists (Daridorexant, Lemborexant and Suvorexant) are not suitable due to their sleep-inducing effects; therefore, 0X1 selective antagonist developed with a sufficient window to 0X2-mediated effects. Emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, and vigilance are linked to 0X1 receptor (Lessel et al. J. Chem. Inf. Model. 2021, 61:5893-5905).
  • oxitocin analogues include oxitocin analogues, cannabinoid receptor agonists, controlled-release diazoxide, and tesofensine- metoprolol combination.
  • GW856464 (WO 2005/042541 Al, GSK) was discontinued following phase 1, reportedly because of poor oral bioavailability (GSK MCHR1 antagonist, Last updated 18 April 2011, https://adisinsight.springer.com/drugs/800021434).
  • AMG-076/071 (WO 2004/043958 Al, Tularik/Amgen) was discontinued following a randomized, multiple-dose, placebo controlled, dose-escalation study evaluated the safety, tolerability, and pharmacokinetics.
  • the 40 subjects enrolled did not experience any clinically significant changes in safety parameters including ECGs, vital signs or laboratory results after having been administered daily doses of 5, 20, 60, 80,120, or 180 mg of AMG 076 for 28 days.
  • Treatment-emergent adverse events were reported in 18 subjects, the most common being headache, dizziness and decreased appetite (AMG 076, Last updated 10 September 2008 https://adisinsight.springer.com/drugs/800019931).
  • NGD-4715 (WO 2006/009789 A2) twice daily for 14 days and in follow up for 14 days. No serious adverse events were observed, however, vivid dreams and awakenings were reported by 50% during week 1. Following the data, Neurogen decided not to advance the compound into phase II testing (http ://adisinsight. springer.com/downloads/mediarelease/ 1817/809084129.html) .) .
  • ALB-127158 (WO 2009/089482 Al, Albany) was discontinued following a phase 1 clinincal trial. It was reportedly safe, well-tolerated and at the end of the 14-day MAD >45% reduction in appetite and meal size was observed in overweight patients (Moore et al., Neurobiol Disease 2014, 61:47-54). The same compound later was advertised as a phase 2- ready asset (CSTL100) by Consynance with the indication of obesity, NAFLD and inflammatory bowel disease (Consynance accessed at 14.06.2022., https://www.consynance.com/phase-2-ready-assets).
  • HBS-102 Harmony Biosciences acquired it as a new asset (named HBS-102) in 2021 for the treatment of narcolepsy and other rare neurological diseases. Since then, no further development was reported (HBS, accessed at 14.06.2022 https ://www .harmonybiosciences .com/science)
  • the primary outcome was safety - there was no discernible effect on food intake, and the drug increased body weight. Development was terminated due to the lack of efficacy and weight gain (October 23-25, 2012 Metabolic Disease Drug Development - A Hanson Wade Conference, Boston, MA, USA Yie J).
  • the melanin-concentrating hormone plays a multifaceted role in energy homeostasis and being central to the control of hypothalamic food intake and energy expenditure (Pissios et al., Endocr Rev 2006, 27(6):606-620).
  • the neuropeptide mainly produced in the lateral hypothalamus, and the far-reaching axons of these mainly glutamatergic neurons supplies higher cortical areas, limbic structures and basal ganglia, but i also medullar and spinal regions (Saito et al., J Comp Neurol. 2001 Jun 18, 435(l):26-40; Schneeberger et al., Mol Meatab 2018, 13:83-89).
  • the cognate receptor of MCH is the GPCR MCHR1 and its less characterized variant MCHR2 (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Sailer et al., Proc NatlAcad Sci USA. 2001, 98(13):7564-7569).
  • MCHRs are widely but unevenly expressed in the mammalian brain but are also present in some peripheral tissues like pancreas, GI tract or reproductive organs.
  • MCHR1 is associated with Gaq/11 and Gai/o while MCHR2 only with Gaq (Saito et al., J Comp Neurol.
  • MCH has attracted considerable attention because of its effects on food intake and body weight and its receptor MCHR1 is still one of the viable targets for obesity therapy (Pissios P., Peptides 2009, 30(l l):2040-2044). MCH is one of the most potent central stimulators of feeding, regulates energy balance and mood (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Pissios et al., Endocr Rev 2006, 27(6):606-620; Forray C., Curr Opin Pharmacol 2003, 3: 85-89; Qu et al., Nature 1996, 380: 243-47; Hervieu G., Expert Opin Ther Targets 2003, 7: 495-511; Chung et al., J Mol Neurosci 2011, 43:115-21).
  • MCHR1 antagonists Structurally different MCHR1 antagonist are known in the art.
  • a group of MCHR1 antagonists contain an optionally substituted (het)aryl-methylene-oxy-pyridinone moiety e.g., as described in WO 2007/018248 Al, WO 2010/141539 Al, WO 2011/127643 Al, or WO 2015/005489 Al.
  • said moiety is linked to a tricyclic group having at least one basic nitrogen e.g., as described in WO 2009/089482 Al, or WO 2016/166684 Al.
  • PWS is a neurodevelopmental disorder that, up to now, best describes the link between metabolism, sleep and imprinted genes.
  • PWS results from the loss of a cluster of paternally expressed genes on the chromosome 15ql 1— ql3 region, many of which are highly expressed in the hypothalamus and characterized by sleep-wake (rapid eye movement [REM] alterations) and metabolic (hyperphagia) abnormalities (Tucci V., PLoS Genet 2016, 12(5): el006004; Tucci et al., Cell 2019, 21:952-965).
  • REM rapid eye movement
  • SNORD116 in neurons derived from induced pluripotent stem cells from PWS patients showed reduced levels of nescient helix loop helix2 (NHLH2) and the prohormone convertase PCI enzyme (PCSK1). NHLH2 is reported to promote Pcskl expression which in turn promotes the conversion of prohormones into mature hormones. The failure of proper hormone maturation may contribute to the various neuroendocrine phenotypes seen in PWS.
  • SNORD116 as a translational regulatory RNA has a major impact on prenatal development of hypothalamic cells and among others mainly orexinergic (ORX) neurons are depleted to 40% in PWS mice.
  • MCH and ORX neurons are anatomically and functionally intermingled and there is considerable overlap between their projection areas (Saito et al., J Comp Neurol. 2001 Jun 18;435(l):26-40; Kilduff TS., J Comp Neurol 2001, i
  • Uncontrollable appetite, weight gain and impaired reproduction in PWS may be explained by overactive MCH neurons as the “checks and balances” lost because of the reduced ORX population in the lateral hypothalamus. Inhibition of MCHR1 on the remaining ORX cells might lead to restoration of the sleep and arousal abnormalities, as well as regaining control over hyperphagia and obesity driven by unleashed MCH signaling (Linehan et al., Mol. Meatabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305-316).
  • ORX neurons decrease their firing during eating and remain in a depressed state throughout the entire eating phase (Gonzalez et al., Current Biol. 2016, 26:2486-2491; Gonzalez et al., Nature Communications 2016, 7:11395).
  • DIO diet-induced obese mice
  • ORX neurons receive an increased excitatory drive and may mediate the rewarding aspect of HFD consumption.
  • ORX signaling diminishes and the increase in excitatory inputs to MCH neurons contribute to the development and maintenance of DIO (Kilduff and de Lecca, J. Comp Neurol 2001, 435:1-5).
  • growth hormone supplementation does not improve behavioural disturbances including hyperphagia (Davies PSW., Int J Obesity 2001, 25:2-7; Yang X., Neuropeptides 2020, 83:102084).
  • SSRIs serotonin reuptake inhibitors
  • Other classes of psychotropic drugs including neuroleptics may be useful in treatment of behavioral symptoms, but their benefits must be weighed against their potential weight-promoting side effects.
  • glucagon-like peptide- 1 (GLP-1) receptor agonists for individuals with PWS have been described in case reports (Goldman et al., J. Clin. Med. 2021, 10, 4540) with mild-moderate weight loss in individual cases, but existing evidence is insufficient to recommend their use in this population and broader use is limited by tolerability. Recently, it was confirmed in a randomized controlled clinical trial that liraglutide is not effective in reducing hyperphagia in PWS (https://www.clinicaltrialsregister.eu/ctr- search/trial/2014-004415-37/results). This must be the case with semaglutide, beyond beneficial effect on BMI, clinical efficacy over hyperphagia has not yet been demonstrated so far.
  • GLP-1 glucagon-like peptide- 1
  • Metformin therapy may suppress appetite, food-related anxiety, and sense of satiety but only in selected individuals with elevated insulin levels due to insulin resistance in females but completely lacks efficacy in males with PWS (Miller JL, J Pediatr Endocrinol Metab. 2014 Jan 1, 27(0): 23-29).
  • PWS patients undergoing weight loss surgery 63 percent of those undergoing gastric bypass had poor weight loss. There may be some long-term efficacy for the most malabsorptive of these procedures, but these operations also confer increased risks because of chronic malabsorption of micronutrients and electrolytes. Patients with PWS may be at particularly high risk after operations causing malabsorption because they already have an increased risk for osteoporosis (Scheimann AO, J Pediatr Gastroenterol Nutr. 2008, 46(l):80). Surgical interventions in patients with PWS cannot be generally recommended, indeed.
  • the disclosure is based on the unexpected discovery that MCHR1 antagonists can be effective in treating PWS.
  • the present invention relates uses of a melanin-concentrating hormone receptor 1 (MCHR1) antagonist, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the treatment of Prader-Willi Syndrome (PWS), for improving, alleviating or delaying progression of one or more symptoms of PWS, such as hyperphagia, for maintaining or reducing body weight, or for reducing food intake in a patient afflicted with PWS.
  • MCHR1 melanin-concentrating hormone receptor 1
  • PWS Prader-Willi Syndrome
  • the present invention relates to certain MCHR1 antagonist, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for use in the treatment of PWS.
  • the MCHR1 antagonist is a compound of formula (I) wherein
  • A is CH, or nitrogen
  • R is hydrogen, halogen, or Ci-6 straight or branched chain alkyl group
  • R 1 is hydrogen, halogen, Ci-6 straight or branched chain alkyl group, Ci-6 straight or branched chain alkoxy group, or mono- or polyhalogenated Ci-6 straight or branched chain haloalky 1 group;
  • R 2 is hydrogen, halogen, Ci-6 straight or branched chain alkyl group, Ci-6 straight or branched chain alkoxy group or mono- or polyhalogenated C1-4 straight or branched chain haloalky 1 group;
  • R 3 is hydrogen, Ci-6 straight or branched chain alkyl group optionally substituted with C3-6 cycloalkyl group, or mono- or polyhalogenated C1-6 straight or branched chain haloalkyl group; C3-6 cycloalkyl group, or C1-6 straight or branched chain alkanoyl group; and/or pharmaceutically acceptable salts, and/or geometric isomers, and/or stereoisomers, and/or diastereomers, and/or hydrates, and/or solvates, and/or polymorph modifications thereof.
  • the MCHR1 antagonist is a compound of formula (I) wherein R 1 is hydrogen, halogen, C1-4 straight or branched chain alkyl group optionally mono- or polyhalogenated, or C1-3 alkoxy group; R 2 is hydrogen, halogen, trifluoromethyl or C1-3 alkyl group; R 3 is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-6 cycloalkyl group or fluorine, C3-6 cycloalkyl group, C1-4 straight or branched chain alkanoyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, halogen, C1-4 straight or branched chain alkyl group optionally mono- or polyhalogenated, or C1-3 alkoxy group
  • R 2 is hydrogen, halogen, trifluoromethyl or C1-3 alkyl group
  • R 3 is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-6 cycloalkyl group or fluorine,
  • the MCHR1 antagonist is a compound of formula (I) wherein R 1 is hydrogen, fluorine, chlorine, methoxy or trifluoromethyl group; R 2 is hydrogen, fluorine, chlorine, or methyl group; R 3 is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-4 cycloalkyl group or fluorine, C3-4 cycloalkyl group, or acetyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, fluorine, chlorine, methoxy or trifluoromethyl group
  • R 2 is hydrogen, fluorine, chlorine, or methyl group
  • R 3 is hydrogen, C1-4 straight or branched chain alkyl group optionally substituted with C3-4 cycloalkyl group or fluorine, C3-4 cycloalkyl group, or acetyl group
  • R is hydrogen, or a pharmaceutically acceptable salt thereof.
  • the MCHR1 antagonist is a compound of formula (I) wherein R 1 is hydrogen, fluorine or chlorine; R 2 is hydrogen; R 3 is methyl, ethyl, isopropyl, cyclopropylmethyl, cyclobutyl or fluoroethyl group; and R is hydrogen, or a pharmaceutically acceptable salt thereof.
  • the MCHR1 antagonist is a compound of formula (I) wherein R 1 is fluorine or chlorine; R 2 is hydrogen; R 3 is isopropyl or cyclopropylmethyl; R is hydrogen and A is nitrogen, or a pharmaceutically acceptable salt thereof.
  • the MCHR1 antagonist is selected from the group consisting of: 4- [(5-chloro-pyridin-2-yl)methoxy] - 1 - ⁇ 1H,2H,3H,4H,5H- [ 1 ,4]diazepino[ 1 ,7-a]indol-9-yl ⁇ - 1 ,2-dihydropyridin-2-one,
  • the MCHR1 antagonist is 4-[(5-chloropyridin-2- yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2- dihydropyridin-2-one in free form (referred to hereinafter as Compound A), or in a pharmaceutically acceptable salt form , e.g., the hydrochloride salt.
  • PWS neurodegenerative disease
  • said symptom is mood disorders, such as depression or mania, personality disorders, intellectual disability, anxiety, obsessive compulsive disorders, cognitive impairment, psychomotor retardation, irritability, bulimia, hyperphagia, extensive daytime sleepiness, obstructive sleep apnea, narcolepsy, catalepsy, hypogonadism, hypothyreosis, ii hyperthyreosis, decreased growth hormone secretion, impaired glucose tolerance, increased fasting glucose, prediabetes, diabetes mellitus (including insulin dependent and non-insulin- dependent), hyperglycaemia, hyperlipidaemia, hypertrigliceridaemia, hypercholesterinaemia, atherosclerosis, coronary artery disease (CAD), peripheral arterial disease (PAD), cerebrovascular arteriosclerosis, NAFLD, NASH, renal failure, loss of bone mineral density, short stature, muscular hypotonia, inflammatory conditions of the skin, more particularly hyperphagia.
  • mood disorders such as depression or mania,
  • one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS refers to prescription or “over the counter” (OTC) drugs or food supplements for weight loss or appetite suppression (such as orlistat, phentermine, topiramate, lorcaserine, bupropion, naltrexone, liraglutide, semaglutide etc.), herbal, fungal or animal extracts irrespectively of origin; antidiabetics (such as insulin, insulin analogues, glucagon, metformin, inhibitors of SGLT2, sulphonylureas, thiazolidinediones, amylin receptor agonists, glucagon-like peptide (GLP) 1 agonists, glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) agonists), antidepressants (such as tricyclics, SSRIs, SNRIs, SDRIs, MAO inhibitors, derivates of melaton
  • OTC over the counter
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration, in the same composition or at the same time.
  • pharmaceutical composition refers to a mixture of a compound of the invention with other chemical components, such as pharmaceutically acceptable excipients e.g., diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to the subject.
  • compositions of the present invention can be formulated in many ways, for instance as tablet, capsule, powder, granules, suspension, emulsion, solution, syrup, aerosol (with a solid or a liquid carrier) soft or hard gelatin capsule, suppository, injection.
  • pharmaceutical composition is formulated as a tablet or a capsule.
  • the pharmaceutical compositions can be in single dosage forms containing predetermined amount of active ingredient.
  • This dosage can contain the therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, or a given percentage of the therapeutically effective amount in such a way that these single dosage forms for repeated administration can be administered over a given period of time in order to reach the desired therapeutically effective dose.
  • Preferred single dosage forms are those which contain the daily dose or sub-dose or - as it was mentioned above - a given percentage of the active ingredient.
  • these pharmaceutical compositions can be manufactured by methods known in the art.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a MCHR1 antagonist and one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS, are administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g., a MCHR1 antagonist and one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the patient.
  • active ingredients e.g., a MCHR1 antagonist and one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS
  • terapéuticaally effective amount refers to the amount of the active ingredient - compared to the subject, who did not receive such an amount - which results in the treatment, curing, prevention, alleviation or improvement of an illness, pathological condition, side-effect, one or more symptoms of a disease, such as hyperphagia, for maintaining or reducing body weight or for reducing food intake, or suppresses, or delay the degree of progression of an illness, pathological condition or one or more symptoms of a disease, such as hyperphagia.
  • the term includes the effective amounts required for improving normal physiological functions as well.
  • a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form
  • a MCHR1 antagonist can be administered in therapeutically effective amount as unformulated drug substances or the active ingredient can be formulated as medicament.
  • the exact therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form depends on several factors, including - but not exclusively - the age and the bodyweight of the treated subject (patient), the type and the seriousness of the disease to be treated, the type of the pharmaceutical composition/medicament and the way of administration.
  • the therapeutically effective amount of a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of at least about 2.5 mg.
  • the therapeutically effective amount of a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of from about 2.5 mg to about 22.5 mg.
  • the therapeutically effective amount of a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of from about 2.5 mg to about 7.5 mg.
  • the therapeutically effective amount of a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form, is a daily dose of about 2.5 mg, about 5 mg or about 7.5 mg.
  • a MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, administered per day.
  • pharmaceutically acceptable salts such as the hydrochloride salt of Compound A
  • the daily dose is also expressed with the equivalent amount of free base.
  • an effective amount refers to an amount of a drug or active ingredient which is sufficient, in the subject to which it is administered, to elicit the biological or medical response of a tissue, system, animal (including human) that is being sought, for instance, by a researcher or clinician.
  • subject refers to a patient in need of method for treatment, curing, prevention, alleviation or improvement of PWS or one or more symptoms, such as il hyperphagia, thereof, for maintaining or reducing body weight or for reducing food intake, or suppressing, or delaying the degree of progression of the illness, pathological condition or one or more symptoms thereof.
  • MCHR1 antagonist e.g., a compound of formula (I) in free form, such as Compound A, or in a pharmaceutically acceptable salt form
  • MCHR1 antagonist can be administered by any appropriate route, for example, by the oral, rectal, transdermal, subcutaneous, local, intravenous, intramuscular, or intranasal route.
  • Preferable administration route is oral.
  • the present invention provides:
  • a method for treating PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • a method for improving, alleviating or delaying progression of one or more symptoms of PWS, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above.
  • MCHR1 antagonist is administered once daily.
  • a method as defined above comprising co-administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a MCHR1 antagonist and one or more additional therapeutic agents effective for treating or alleviating one or more symptoms of PWS.
  • a pharmaceutical composition for use in any one of the methods 1.1 to 1.7 comprising a MCHR1 antagonist, e.g., a compound of formula (I) as defined hereinabove, together with one or more pharmaceutically acceptable excipients.
  • a pharmaceutical combination for use in any one of the methods 1.1 to 1.7 e.g., a kit, comprising a) a first agent which is a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above, and b) one or more additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS as indicated above, wherein the kit may comprise instructions for its administration.
  • a first agent which is a MCHR1 antagonist, e.g., a compound of formula (I) as defined herein above
  • additional therapeutic agents effective at treating or alleviating one or more symptoms of PWS as indicated above
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above, for use in any one of the methods 1.1 to 1.7.
  • a MCHR1 antagonist e.g., a compound of formula (I) as defined herein above, for use in the preparation of a medicament for any one of the methods 1.1 to 1.7.
  • MCHR1 antagonist e.g., a compound of formula (I) as defined herein above, for any one of the methods 1.1 to 1.7.
  • the MCHR1 antagonists as described herein e.g., Compound A, is useful for treating hyperphagia in a patient afflicted with PWS.
  • MCHR1 antagonists e.g., the MCHR1 antagonists according to formula (I), as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.
  • Compound A is a selective MCHR1 antagonist displaying high affinity for the human MCHR1 receptor (Ki: 45.3 ⁇ 6.6 nM), its IC50 value in functional assays of human receptor (such as described in WO 2016/166684 Al) is nanomolar (6.2 ⁇ 0.7 nM) and it has more than 1.500-fold greater potency at the MCHR1 than the MCHR2 receptor.
  • Compound A exerted pharmacological activities that are consistent with its in vitro effects.
  • Compound A displayed dose-dependent, anti-obesity activity in rodent model of obesity.
  • mice Male C57B1/6J mice were fed with 60% caloric content of fat diet ad libitum for 12 weeks prior to the study to reach 40-45 g body weight. Following the weight-gain phase 14- day long oral treatment (twice a day) with Compound A induced a dose-dependent body weight loss in the 0.01-3 mg/kg dose range in DIO mice. The minimal effective dose (MED) was 0.3 mg/kg. The reduction of cumulative caloric intake (cCI) became significant at doses 1 and 3 mg/kg.
  • MED minimal effective dose
  • cCI cumulative caloric intake
  • Diet-induced obese (DIO) beagle dogs are very sensitive to Compound A, 0.6 mg/kg, once daily per os has strong inhibition of food intake and robust body weight reduction.
  • the MED and side effect free 0.02 mg/kg dose are associated with 1.2 ng/ml exposure at the last (7th) day of treatment.
  • Dog is a species having both MCHR1 and MCHR2 receptors similarly to humans.
  • Adult male beagle dogs (3.5-year-old) were ad libitum fed with high energy diet (30% fat/20% protein) for 10 weeks to establish diet induced obesity.
  • DIO dogs (mean body weight: 16.4 kg) were treated orally in five phases.
  • 8 animals were treated orally (in capsule), once a day with 0, 0.02, 0.06, 0.2 or 0.6 mg/kg doses of Compound A, for 7 days followed by a 14-day washout phase in a cross-over method.
  • the same high energy diet was applied during the full 105-day treatment period.
  • Treatment with Compound A induced significant and dose-dependent body weight loss compared to vehicle in all treated groups.
  • the body weight reduction reached its maxima at 1-3 days post-treatment.
  • the maximal mean body weight change was -10,4 ⁇ 2,2% at the 0.6 mg/kg/day dose on washout day 3 (p ⁇ 0.001).
  • Non-human primate studies provided competitive data on metabolic efficacy of Compound A.
  • Compound A (0.06, 0.3, 1.5 mg/kg. i.m., 25% HPBCD formulation) and exenatide (Byetta, 2 pg/kg, s.c.; serving as positive control) were applied for 5 consecutive dosing days. There were 2 food intake (FI) sessions: SI (120 min) followed by S2 (60 min) with 1-hour delay. Injections were done at Ih prior SI. One-week washout was allowed after each treatment week. High dose of Compound A (1.5 mg/kg) was based on the results of previous rhesus tolerability study.
  • MCHR1 antagonists such as Compound A, e.g., hydrochloride salt thereof are potent MCHR1 full antagonists both in vitro and in vivo.
  • MCHR1 antagonists such as Compound A, e.g., hydrochloride salt thereof displays anti-obesity and food intake inhibitory effect in a variety of animal disease models.
  • Table 3 shows human plasma exposures (geometric means) obtained from the phase
  • a MCHR1 antagonist e.g., a compound of formula (I), such as Compound A, e.g. hydrochloride salt thereof.
  • Part A to assess short-term efficacy for the treatment of hyperphagia in PWS.
  • Part B to assess the efficacy of different doses for the treatment of hyperphagia in PWS.
  • Part B Multicentre, 13-week, placebo-controlled, randomized parallel, 4-arm study
  • Part A approximately 66 patients
  • Part B approximately 110 patients
  • Part A 22.5 mg once daily
  • Part B 2.5 mg, 5 mg, or 7.5 mg once daily li
  • the general clinical state of the patients is investigated by physical (vital signs, height, weight, BMI, waist circumference etc.) and laboratory examinations (hematology, clinical chemistry, coagulation and lipids, urinalysis,).
  • CGI-S Clinical Global Impression-Severity
  • CGI-I Clinical Global Impression - Improvement
  • Active substance(s) 0.001 - 50%
  • Active substance(s) 0.0003 - 50% Suppository base 1 - 99.9% Surface-active agents 0 - 20% Lubricant 0 - 20% Preservatives q.s.

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Abstract

La présente invention concerne des utilisations d'un antagoniste du récepteur 1 de l'hormone concentrant la mélanine (MCHR1), tel que, par exemple, un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, ou des compositions pharmaceutiques de celui-ci pour le traitement du syndrome de Prader-Willi, pour améliorer, atténuer ou retarder un ou plusieurs symptômes du syndrome de Prader-Willi, tels que l'hyperphagie, pour maintenir ou réduire le poids corporel, ou pour réduire la prise alimentaire chez un patient atteint du syndrome de Prader-Willi.
PCT/IB2023/056245 2022-06-17 2023-06-16 Antagonistes de mchr1 pour le traitement du syndrome de prader-willi WO2023242810A1 (fr)

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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106452A2 (fr) * 2002-06-12 2003-12-24 Millennium Pharmaceuticals, Inc. Antagonistes du recepteur de l'hormone de melano-concentration
WO2004043958A1 (fr) 2002-11-06 2004-05-27 Amgen Inc. Composes heterocycliques condenses
WO2005042541A1 (fr) 2003-10-23 2005-05-12 Glaxo Group Limited Derives de 3-(4-aminophenyl)-thienopyrimid-4-one utilises comme antagonistes de mch r1 pour le traitement de l'obesite, du diabete, de la depression et de l'anxiete
WO2006009789A2 (fr) 2004-06-17 2006-01-26 Neurogen Corporation Derives piperazine a substitution aryle
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2009089482A1 (fr) 2008-01-11 2009-07-16 Albany Molecular Research, Inc. Pyridoindoles (1-azinone)-substitués en tant qu'antagonistes mch
WO2009146365A1 (fr) 2008-05-29 2009-12-03 Bristol-Myers Squibb Company Thiénopyrimidinones hydroxy-substituées en tant qu’antagonistes de récepteur 1 de l’hormone concentrant la mélanine
WO2010125390A1 (fr) 2009-05-01 2010-11-04 Astrazeneca Ab Agents thérapeutiques 713
WO2010141539A1 (fr) 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones en tant qu'antagonistes du recepteur 1 de l'hormone de melano-concentration
WO2011058943A1 (fr) * 2009-11-11 2011-05-19 塩野義製薬株式会社 Composition pharmaceutique formée par combinaison d'un composé ayant une activité antagoniste de mchr1 et un composé ayant une activité antagoniste de npy y5
WO2011127643A1 (fr) 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
WO2015005489A1 (fr) 2013-07-09 2015-01-15 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole
WO2021142395A1 (fr) * 2020-01-10 2021-07-15 Consynance Therapeutics, Inc. Polythérapies de médicaments et leurs méthodes d'utilisation

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106452A2 (fr) * 2002-06-12 2003-12-24 Millennium Pharmaceuticals, Inc. Antagonistes du recepteur de l'hormone de melano-concentration
WO2004043958A1 (fr) 2002-11-06 2004-05-27 Amgen Inc. Composes heterocycliques condenses
WO2005042541A1 (fr) 2003-10-23 2005-05-12 Glaxo Group Limited Derives de 3-(4-aminophenyl)-thienopyrimid-4-one utilises comme antagonistes de mch r1 pour le traitement de l'obesite, du diabete, de la depression et de l'anxiete
WO2006009789A2 (fr) 2004-06-17 2006-01-26 Neurogen Corporation Derives piperazine a substitution aryle
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2009089482A1 (fr) 2008-01-11 2009-07-16 Albany Molecular Research, Inc. Pyridoindoles (1-azinone)-substitués en tant qu'antagonistes mch
WO2009146365A1 (fr) 2008-05-29 2009-12-03 Bristol-Myers Squibb Company Thiénopyrimidinones hydroxy-substituées en tant qu’antagonistes de récepteur 1 de l’hormone concentrant la mélanine
WO2010125390A1 (fr) 2009-05-01 2010-11-04 Astrazeneca Ab Agents thérapeutiques 713
WO2010141539A1 (fr) 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones en tant qu'antagonistes du recepteur 1 de l'hormone de melano-concentration
WO2011058943A1 (fr) * 2009-11-11 2011-05-19 塩野義製薬株式会社 Composition pharmaceutique formée par combinaison d'un composé ayant une activité antagoniste de mchr1 et un composé ayant une activité antagoniste de npy y5
WO2011127643A1 (fr) 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
WO2015005489A1 (fr) 2013-07-09 2015-01-15 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole
WO2021142395A1 (fr) * 2020-01-10 2021-07-15 Consynance Therapeutics, Inc. Polythérapies de médicaments et leurs méthodes d'utilisation

Non-Patent Citations (68)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "RGH-706 by Gedeon Richter for Prader-Willi Syndrome (PWS): Likelihood of Approval", PHARMACEUTICAL TECHNOLOGY, 2 September 2023 (2023-09-02), Internet, pages 1 - 2, XP093082751, Retrieved from the Internet <URL:https://www.pharmaceutical-technology.com/data-insights/rgh-706-gedeon-richter-prader-willi-syndrome-pws-likelihood-of-approval/> [retrieved on 20230918] *
ANONYMOUS: "Study to Evaluate Efficacy, Safety, and Tolerability of RGH-706 in Prader-Willi Syndrome - NCT05322096", CLINICALTRIALS.GOV, 25 March 2022 (2022-03-25), Internet, pages 1 - 7, XP093082796, Retrieved from the Internet <URL:https://www.clinicaltrials.gov/study/NCT05322096?term=NCT05322096&rank=1&tab=table> [retrieved on 20230918] *
BARSON ET AL., INT J ENDOCRINOL, vol. 2013, 2013, pages 983 - 64
BELLIS ET AL., EUR J MED GENET., vol. 65, no. 1, January 2022 (2022-01-01), pages 104379
BIETH ET AL., EUR. J. HUMAN GENET., vol. 23, 2015, pages 252 - 255
CARIASWEVRICK, MOLECULAR THERAPY: METH. & CLIN. DEV., vol. 13, 2019, pages 344 - 358
CARREL AL., J CLIN ENDOCRINOL METAB, vol. 87, no. 1581, 2002, pages 114
CHEN ET AL., BIOORG MED CHEM LETT, vol. 22, no. 1, 2012, pages 363 - 366
CHEON CK., ANN. PEDIATR. ENDOCRINOL. METAB., vol. 21, 2016, pages 126 - 135
CHUNG ET AL., J MOL NEUROSCI, vol. 43, 2011, pages 115 - 21
CHUNG ET AL., OPEN BIOL, vol. 10, 2020, pages 200195
CHUNG ET AL., OPEN BIOLOGY, vol. 10, 2020, pages 200195
CONSOLI A ET AL., RANSL PSYCHIATRY., vol. 9, 2019, pages 274
CRINO ET AL., DIABETES METAB SYNDR OBES., vol. 11, 2018, pages 579 - 593
DAVIES PSW., INT J OBESITY, vol. 25, 2001, pages 2 - 7
DE WAELE ET AL., EUR J ENDOCRINOL., vol. 159, no. 4, October 2008 (2008-10-01), pages 381 - 8
DUKER ET AL., EUR. J. HUM. GENET., vol. 18, 2010, pages 1196 - 201
FORRAY C., CURR OPIN PHARMACOL, vol. 3, 2003, pages 85 - 89
GOLDMAN ET AL., . CLIN. MED., vol. 10, 2021, pages 4540
GONZALEZ ET AL., CURRENT BIOL., vol. 26, 2016, pages 2486 - 2491
GONZALEZ ET AL., NATURE COMMUNICATIONS, vol. 7, 2016, pages 11395
GUNAY-AYGUN ET AL., PEDIATRICS, vol. 108, 2001, pages E95
HASSANI ET AL., PNAS, vol. 106, 2009, pages 2418 - 2422
HERVIEU G., EXPERT OPIN THER TARGETS, vol. 7, 2003, pages 495 - 511
HILL ET AL., J BIOL CHEM, vol. 276, no. 23, 2001, pages 20125 - 20129
HOLM ET AL., PEDIATRICS, vol. 91, 1993, pages 398 - 402
KAYADJANIAN ET AL., PLOS ONE, vol. 16, no. 3, pages e0248739
KILDUFF TS., J COMP NEUROL, vol. 435, 2001, pages 1 - 5
KILDUFFLECCA, J. COMP NEUROL, vol. 435, 2001, pages 1 - 5
KOHN Y., INT J EAT DISORD, vol. 30, 2001, pages 113 - 117
LASSI ET AL., SLEEP, vol. 39, 2016, pages 637 - 44
LESSEL ET AL., J. CHEM. INF. MODEL., vol. 61, 2021, pages 5893 - 5905
LINEHAN ET AL., J. PHYSIOL, vol. 596, 2022, pages 305 - 316
LINEHAN ET AL., MOL. MEATABOLISM, vol. 36, 2020, pages 100977
MANZARDO ET AL., AM J GENET., vol. 170, 2016, pages 2328 - 2333
MCCANDLESS ET AL., DIABETES OBES METAB., vol. 19, no. 12, December 2017 (2017-12-01), pages 1751 - 1761
MILER ET AL., J CLIN ENDOCRINOL METAB, vol. 107, no. 6, 17 May 2022 (2022-05-17), pages e2373 - e2380
MILLER ET AL., AM J MED GENET A., vol. 155, no. 5, May 2011 (2011-05-01), pages 1040 - 9
MILLER JL, J PEDIATR ENDOCRINOL METAB., vol. 27, no. 0, 1 January 2014 (2014-01-01), pages 23 - 29
MOORE ET AL., NEUROBIOL DISEASE, vol. 61, 2014, pages 47 - 54
OBATA K., J PEDIATR ENDOCRINOL METAB., vol. 16, no. 2, 2003, pages 155
OMOKAWA ET AL., AM. J. GENET A., vol. 170A, 2016, pages 1181 - 6
PACE ET AL., HUM. MOL. GENET., vol. 29, 2020, pages 2051 - 2064
PACE M., J CI INSIGHT, vol. 5, 2020, pages e137495
PACE M., JCI INSIGHT, vol. 5, 2020, pages el37495
PISSIOS ET AL., ENDOCR REV, vol. 27, no. 6, 2006, pages 606 - 620
PISSIOS ET AL., ENDOCRINOLOGY, vol. 144, no. 8, 2003, pages 3514 - 3523
PISSIOS P., PEPTIDES, vol. 30, no. 11, 2009, pages 2040 - 2044
POLLEX-WOLF ET AL., J. CLIN. INVEST., vol. 128, 2018, pages 960 - 969
QU ET AL., NATURE, vol. 380, 1996, pages 243 - 47
RESNICK ET AL., MAMM GENOME., vol. 24, 2013, pages 165 - 178
ROKOSZHOBBS, DRUG NEWS PERSPECT, vol. 19, no. 5, 2006, pages 273 - 286
SAILER ET AL., PROC NATLACAD SCI USA., vol. 98, no. 13, 2001, pages 7564 - 7569
SAITO ET AL., J COMP NEUROL., vol. 435, no. 1, 18 June 2001 (2001-06-18), pages 26 - 40
SAITOMARUYAMA, J EXP ZOOL COMP EXP BIOL, vol. 305, no. 9, 2006, pages 761 - 768
SCHEIMAN AO., CLINICAL FEATURES, DIAGNOSIS, AND TREATMENT OF PRADER-WILLI SYNDROME, 31 January 2022 (2022-01-31), Retrieved from the Internet <URL:https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatment-of-prader-willi-syndrome/print>
SCHEIMANN AO, J PEDIATR GASTROENTEROL NUTR., vol. 46, no. 1, 2008, pages 80
SCHNEEBERGER ET AL., MOL MEATAB, vol. 13, 2018, pages 83 - 89
SHAPIRA AN., AM J MENT RETARD., vol. 109, no. 4, 2004, pages 301
SHEPHERD ET AL., GENES, vol. 11, 2020, pages 128
SMITH ET AL., HUM. MOL. GENET., vol. 18, 2009, pages 3257 - 65
SWAAB DF., ACTA PAEDIATR SUPPL., vol. 423, 1997, pages 50 - 54
TSAI ET AL., MDM POLICY PRACT., vol. 6, no. 2, 2021, pages 23814683211039457
TUCCI ET AL., CELL, vol. 21, 2019, pages 952 - 965
TUCCI V., PLOS GENET, vol. 12, no. 5, 2016, pages e1006004
VITALI ET AL., J CELL SCI., vol. 123, 2010, pages 70 - 83
YANG X., NEUROPEPTIDES, vol. 83, 2020, pages 102084
YIE J: "Metabolic Disease Drug Development", A HANSON WADE CONFERENCE

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