P4934 PC00/108725 G00055
`
`Treatment of Proteinuria
`
`Cross-Reference to Related Applications
`
`This application is a continuation-in-part of international Application No.
`
`PCTIEP2019/066578, filed June 24, 2019, which claims the benefit of EP 18179319.1,
`
`filed June 22, 2018, the entireties of whichare incorporated by reference herein.
`
`Technicalfield
`
`10
`
`The present invention relates to a composition comprising a compound of formula (5,
`
`dia} or GH, or a pharmaceutically acceptable derivative thereof, for use in a method of
`
`treating kidney disease, especially proteinuric kidney diseases, such as nephrotic
`
`syndromes.
`
`Background
`
`Proteinuria, the hallmark of glomerular injury, is a cammon finding on urinalysis, and is
`
`by liself a strong, independent and modifiable risk factor for end stage renal disease,
`
`premature death of cardiovascular origin, and ischemic stroke in patients with diabetes.
`
`Despite recent advances refractory proteinuria continues to be a challengein clinical
`
`practice. If is imperative to develop more effective modalities to arneliorate glomerular
`
`injury and induce remission of proteinuria. Recent evidence points to melanocortin
`
`system as a novel target for treatment of proteinuria.
`
`Membranous nephropathy (MN) is one of the most common causes of nephrotic
`
`syndrome in adults. One-third of the patients have a good prognosis with spontaneous
`
`remission. Even so, approximately 50%of the remainder manifest an unchanged
`
`disease state, whereas 50% progress into ESRD (end-stage renal disease} and
`
`dialysis. The nephrotic syndrome is a glomerular disease characterized by proteinuria,
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`30
`
`edema, hypoalburninemia, and hyperlipidemia. Mast MN cases are idiopathic and the
`
`mechanisms underlying the disease are still largely unknown. Treatments have
`
`classically been nonspecific and often include steroids with anti-inlammatory actions,
`
`sometimes in combination with cyfotoxic agents. These drugs affect multiple tissues,
`
`causing cytotoxic effects, osteoporosis, adrenal insufficiency, hypertension, peptic
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`

`

`P4934 PC00/108725 G00055
`
`ulcers, and increased risk of glucose intolerance and infections. Therefore, more
`
`effective and specific treatment options are needed.
`
`The melanocortin system is a set of neuropepiidergic and immunoendocrine signaling
`
`pathways that play an integral role in the homeostatic control of a diverse array of
`
`physiological functions, including melanogenesis, stress response, inflammation,
`
`irarnunomodulation and adrenocortical steroidogenesis. It consists of multiple
`
`components, including the five G protein-coupled melanocortin receptors: melanocortin
`
`receptor 1 (MC1R} to MCSR; peptide ligands: a, B, y-melanocyte stimulating hormone
`
`10
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`fa. 8, ¥- MSH), adrenocorticotropic hormone {ACTH} secreted by the anterior pituitary;
`
`and endogenous antagonists. The biological functions of melanocortin sysiem are
`
`mediated by the five melanocartin receptors (MCRs}, which have distinct issue
`
`distribution, convey different signalling anc exert varying biological activities in different
`
`organ systems.
`
`Adrenocarticotropic hormone (ACTH) is an endogenous peptide hormone and agonist
`
`for all melanocorin receptors f to 5 (MC1-5R)}, of which MC2R specifically binds
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`ACTH; steroidogenesis is triggered only by ACTH and mediated via MC2R in the
`
`adrenal cortex. Alpha-melanocyte stimulating harmone (aMSH} is a small endogenous
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`20
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`peptide hormone, structurally related to ACTH, which binds all of the MCRs except
`
`MC2R. MC1R, abundantly expressed by melanocytes in the skin, is a key control point
`
`in melanogenesis and determines hair colour.
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`Melanocortin therapy by using ACTH or non-steroicogenic melanocortin peptides
`
`atienuates proteinuria and glomerular injury in experimental glomerular diseases and
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`induces remission of nephrotic syndrome in patients with diverse glomerulopathies,
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`even those resistant to steroids, including membranous nephropathy (MN}, minimal
`
`change disease (MCD), focal seqmental giomeruloscierosis (FSGS) and igA
`
`nephropathy. The underlying mechanism remains elusive, but the role of melanocortin
`
`38
`
`tT receptor (MCI1R} has been implicated and MCR is heavily and specifically
`
`expressed in human kidney cortex and specific renal cell types including podocytes
`
`iLindskog et al. 2010). However, recent studies have found effects of ACTH
`
`monotherapy and NDP-agM&H (iNle,, D-Phe7}-aMSH} also in patients bearing
`
`dominant-negative MCR mutations, which was confirmed aiso in MC 1R-null mice and
`
`in vitro in primary podocytes derived from MC1R-null and wildtype mice. The anti-
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`P4934 PC00/108725 G00055
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`proteinuric effect of melanccortin signalling thus appears fo be stercidagenic-
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`independent and MC1R-dispensable, and the melanocortin effect might, at least in
`
`part, targel a pathagenic pathway common to all proteinuric kidney diseases.
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`Podocytes are a critical component of the glomerular filtration barrier controlling
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`giornerular permeability and selectivity and are considered a major culprit accounting
`
`for massive proteinuria in diverse glomerular diseases. The beneficial effect of
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`melanocortin therapy is likely attributable to a direct action on podocytes (Qiao et al.
`
`2016).
`
`10
`
`it is at present therefore not possible ta predict which melanacortin agonists and which
`
`associated targets will present as useful candidates for treatment of proteinuric
`
`diseases such as kidney diseases.
`
`Phenyl pyrrole aminoguanidine derivatives with activity on the melanocoriin receptors
`
`are disclosed in WO 2007/441343. One example of such compound is the anti-
`
`inflammatory AP1189 ((E}-A-frans-{3-41-(2-nitfropheny)- 1 H-pyrral-2-yl--allyiidene}-
`
`aminoquanidium acetate) which was first shown to bind the MC1R (WO 2007/141343}
`
`and later wasidentified as a biased dual agonist at receptors MC1R and MC3Rthat
`
`does not provoke canonical cAMP generation (and hence no MC1R-induced
`
`melanogenesis} bul instead appear to induce altemative pathways including ERK1/2-
`
`phosphorylation and Ca** mobilization (Montero-Melendez et al. 2015).
`
`Summary
`
`Fhe present inventors have found that ihe phenyl pyrrale aminoguanidine derivative
`
`APt189 ((E)-A-trans-{3-[1-{2-nitrophenyl}-1H-pyrroi!-2-yihallyiidene}-aminoqguanidium
`
`acetate} significantly reduces proteinuria in Passive Haymann Nephritis, a nephropathy
`
`model, as compared io vehicle, measured as a significant reduction of albumin
`
`excretion rate and FRa» (fraction albumin excretion): and also has a significantly higher
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`30
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`GFR (glomerular fitration rate: creatinine clearance) and a significantly reduced FRap
`
`compared to treatment with ACTH(1-24}. AP1189 and related cormpounds are
`
`candidates for the improved treatment of proteinuric kidney diseases.
`
`ft is an aspect of the present disclosure to provide a composition comprising a
`
`compound of formula (f} or dak
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`

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`P4934 PC00/108725 G00055
`
`4
`
`R;
`HN
`
`ee
`
`;
`
`eR;
`
`H
`
`hh
`
`formula (1)
`
`R3
`
`R3
`
`N
`
`Rs
`
`Ry
`
`Ry
`
`Ry
`
`Ri
`
`
`
`formula Ula}
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`40
`
`forms and racemic forms, thereof
`
`wherein
`
`nis 1, 2or3:
`
`45
`
`

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`P4934 PC00/108725 G00055
`
`each Ry, Re, Rs, Ry and Rsis independently selected fram the group consisting of
`
`hydrogen, optionally substituted C,,¢-alkyl, optionally substituted Cs.s-cycloalkyl,
`
`optionally substitufed Co.-alkenyl, optionally substituted C.yc-alkadienyl, optionally
`
`substituted Cac- alkynyl, hydroxy, optionally substituted C.-c-alkoxy, optionally
`
`substituted Czc-alkenyloxy, carboxy, optionally substituted C:.s-alkoxycarbony|,
`
`optionally substituted C;..- alkylcarbony!, forrnyl, C..-alkylsuiphonylamina, optionally
`
`substituted aryl, optionally substituted arjloxycarbonyl, optionally substituted aryioxy,
`
`optionally substituted aryicarbonyl, optionally substituted arylamine,
`
`aryisuiphonylamino, optionally substituted heteroaryl, optionally substituted
`
`10
`
`heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted
`
`heteroaryicarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamina,
`
`optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbony|,
`
`optionally substitufed heterocyclyloxy, optionally substituted heterocyclyicarbony|,
`
`optionally substituted heterocyclylamino, heterocyclylsulphonylamine, amino, mono-
`
`and ciiC..-alkyiamino, carbamoyl, mono- and di(C..alkyaminocarbonyl, amino-Cy.-
`
`alkyl-aminocarbonyl, mono- and di{(C:<- alkvlaminc-C1s-aikyLaminocarbonyl, Crs-
`
`aikylcarbonylamino, amino-C,.-aiky-+ carbonylamino, mono- and di(Cy.-alkyllamino-Cy.
`
`g-alkyl-carbonylamino, cyano, guanidine, carbamicdo, C;..-alkanoyloxy, Cis
`
`aikyisulohonyl, Cis-alkylsulphinyl, Cy<-alkylsulphonyl- oxy, aminosulfonyl, mono- and
`
`cC..-alkyjaminosulfonyl, nitro, optionally substituted C;.-alkylthio and halogen,
`
`where any nitragen-bound C:s-alkyi is optionally substitufed with hydroxy, C1<-alkoxy,
`
`Caealkenyloxy, amino, mone- and diiC..-aikyllamino, carboxy, Cis-
`
`aikyicarbonylaming, halogen, C1.-alkylthio, C.-.-alky-sulphonyl-amino or quanidine:
`
`each Re and Re is independently selected from the aroup consisting of hydrogen,
`
`optionally substituted C:-c-alkyl, optionally substituted Co-s-alkenyl, optionally
`
`substituted C,.- alkacieny!, optionally substituted C.-c-alkynyl, optionally substituted
`
`Cre-aikoxycarbonyl, optionally substituted C..alkyicarbonyi, optionally substituted
`
`aryl, optionaily substituted aryloxycarbony!, optionally substituted aryicarbony(,
`
`30
`
`optionally substitufed heteroaryl, optionally substituted heteroaryloxycarbony|,
`
`optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di{Cy<-
`
`alkyaminocarbonyl, amino- C:<-alkyl-aminocarbonyl and mono- and di{C+s-
`
`aikyhamino- C.,-alkyl-aminocarbonyl or Re and Ry may together form a five- or six-
`
`membered nitrogen-containing ring;
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`

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`P4934 PC00/108725 G00055
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatment of a kidney
`
`disease.
`
`ft is also an aspect of fhe present disclosure to provide a compasition comprising a
`
`compound of formula (i):
`
`ON
`
`Hg
`
`formula (1)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`10
`
`forms and racemic forms, thereof:
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatment of a kiiney
`
`disease.
`
`$5
`
`itis also an aspect of the present disclosure to provide a composition comprising a
`
`compound selected fram the croup consisting of {3-[1-(2-nitropheny!}-1H-pyrral-2-y4]}-
`
`allylidenel-aminoquanidine; §3-[1-(2-nitraphenyb-1 H-pyrrob2-yi-allwidene}-
`
`aminoguanidinium acetate; (E)-A-irans-{3-{1-(2-nitropheny!)-1 H-pyrrol-2-yi-allylidene}-
`
`aminoguanidine: and (E)-Atfrans-<{3-[1-(2-nitrophenyl)-1H-pyrral-2-yiallylidene}-
`
`20
`
`aminoguanidinium acetate (AP1189), or a pharmaceutically acceptable derivative
`
`thereof, for use in the treatment of a kidney disease.
`
`in one embodiment said kidney disease is a kidney disease that present with
`
`proteinuria.
`
`25
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`

`

`P4934 PC00/108725 G00055
`
`in one embodiment said kidney disease is a glomerular disease, such as a disease
`
`affecting the podocytes of the glomerull.
`
`in one embodiment said kidney disease is nephrotic syndrome iglomerulonephrosis}.
`
`such as primary nephrotic syndrome or secondary nephrotic syndrome.
`
`Also provided is a compound of the disclosure, for example, {3-[1-(2-nitrophenyl}-1H-
`
`pyrrol-2-yil-allylidenel-aminoaquanicdine:; {3-[1-{2-nitroshenyl}-1H-pyrrol-2-yl]-allyiidene}-
`
`aminoguanidinium acetate; (E)-A-irans-{3-11-(2-nitropheny!)}-1 H-pyrral-2-yi]-allvlidene}-
`
`10
`
`aminoquanidine: and (£)-N-trans-{3-[1-(2-nitrophenyl)}-1H-pyrrol-2-yi-allylidene}-
`
`aminoguanidinium acetate (AP1189), or a tautomeric form thereof, or a
`
`pharmaceutically acceptable salt thereof, for usein treating membranous nephropathy,
`
`for example idiopathic membranous nephropathy (iMN}.
`
`Definitions
`
`The term “pharmaceutically acceptable derivative” in the present context includes
`
`pharmaceutically acceptable salts, which indicate a salt which is not harmful fo the
`
`patient. Such salts include pharmaceutically acceptable basic or acid addition salis as
`
`well as pharmaceutically acceptable metal salts, ammonium salts and alkylated
`
`ammonium salts. A pharmaceutically acceptable derivative further includes esters and
`
`prodrugs, or other precursors of a compound which may be biologically metabolized
`
`into the active compound, or crystal forms of a compound.
`
`The term “acid addition salt" is intended to include “pharmaceutically acceptable acid
`
`addition salt" which indicates saits which are not harmful to the patient. Acid addition
`
`salts include salts of inorganic acids as well as organic acids. Representative examples
`
`of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric,
`
`sulfuric, nitric acics and the like. Representative examples of suitable organic acids
`
`incluce formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,
`
`furmaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
`
`30
`
`Salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,
`
`bismethylene salicylic, ethanedcisulfonic, gluconic, citraconic, aspartic, stearic, palmitic,
`
`EDTA, glycolic, p-aminobenzaic, giulamic, benzenesulfonic, p-toluenesulfonic acids
`
`and the lke. Further examples of pharmaceutically acceptable inorganic or organic acid
`
`addition salts include the pharmaceuticaily acceptable salts listed in J. Pharm. Sci. 66,
`
`2, {1977} which is incorporated herein by reference.
`
`

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`P4934 PC00/108725 G00055
`
`Fhe term "therapeutically effective amount" of a compound as used herein refers to an
`
`amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the
`
`clinical manifestations of a given disease or disorder and iis complications. An amount
`
`adequate to accomplish this is defined as “therapeutically effective amount". Effective
`
`amounts for each purpose will depend on the severity of the disease or injury as well
`
`as the weight and general state of the subject. It will be understood that determining an
`
`appropriate dosage may be achieved using routine experimentation, by constructing a
`
`matrix of values and testing different points in the matrix, which is all within the ordinary
`
`skills of a trained physician or veterinary.
`
`30
`
`The terms “treatment” and “treating” as used herein refer to the management and care
`
`of a subject (aiso referred to herein as a patient) for the purpose of combating a
`
`condition, disease or disorder. The term is intended to include the full spectrum of
`
`treatments far a given candition from which the subject is suffering. The subject to be
`
`treated is preferably a mammal, in particular a human being. Treatment of animals,
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`such as mice, rats, dogs, cats, horses, cows, sheep and pigs, is, however, also within
`
`the scope of the present context. The subject to be treated can be of various ages.
`
`Description of Drawings
`
`Figure 1: Rats treated with fest compound 1 {(AP1189. (/£)-A-irans-(3-f1-(2-
`
`nitrophenyl}-1H-pyrroh-2-yi-allyiidenel-aminoquanidium acetate) have a significant
`
`reduction in proteinuria af day 28 anc day 42 compared to control rats (vehicle).
`
`Control rats maintained an unchanged albumin excretion at all time points, whereas
`
`rats treated with test compound 4 showa 3146%: reduction in albumin excretion rate at
`
`day 28 and a 46210% reduction in albumin excretion rate at day 482. See Examples
`
`for details.
`
`Figure 2A} Rats treated with test compound 1 (AP 1189: (/6)-A-iranst{3-[1{2-
`
`nitrophenyl}-1H-pyrrol-2-yi-allylidene}-aminoguanidium acetate} havea significantly
`
`38
`
`higher GFR (creatinine clearance) following 4 weeks treatment than the rats treated
`
`with the positive control (ACTH 1-24):
`
`i}
`
`if}
`
`i}
`
`positive control at 10 mo/day: 2.19 40.24 mL/min
`
`test compound 1 at 20 mg/kg: 3.1240.14 mLimin (p=0.002)
`
`test compound 1 af 40 mavka: 2.9440.14 mL/24 min (p=0.07).
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`

`

`P4934 PC00/108725 G00055
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`Figure 2B} Rats treated with test compound 1 (AP1189: ((E)-A-trans-{3-[7-(2-
`
`nitrophenyl)-1H-pyrrol-2-/f-allylidene}-aminoguanidium acetate} have a significantly
`
`reduced fraction albumin excretion (FEAIb}) compared to positive control (ACTH 1-24):
`
`i}
`
`if}
`
`fii}
`
`positive control at 10 mg/day: 0.5920.02%
`
`test compound 1 at 20 mg/kq: 0.04540.04% (p=0.007)
`
`test compound 1 at 40 mayker: 0.3540.05% {p=0.001}.
`
`Figure 34 depicts Phase 1 Part 4 MAD for an AP1189 suspension of the disclosure at
`
`day 1
`
`10
`
`Figure 3B depicts Phase 1 Part 4 MAD for an AP1189 suspension of the disclosure ait
`
`day 14
`
`Detailed description
`
`Melanocortin (MC) receptors (MC1R-MC5R), a family of class A G protein-coupled
`
`receptors (GPCRs), are attractive therapeutic targets for a number of conditions due to
`
`their wide distribution and diversity of physiological processes they requiate. MC TR
`
`requiates UV light-induced skin tanning and other immuneresponses because ofits
`
`20
`
`expression on leukocytes. MC2R regulates cortisol production on the adrenal glands,
`
`whereas MC5R plays a role on exocrine glands secretions. MC3R and MCA4R exert
`
`non-redundant functions on energy hameosiasis in addition to specific anti-
`
`inflammatory roles: whereas MC3R activation is particularly protective for jaint
`
`inflammation such as arthritis, MC4R provides neuroprotection in brain inflammation.
`
`Accardingly, an array of pathological situationscould be targeted with MCR-drugs
`
`including skin conditions, cardiovascular pathologies, joint inflarnmation, obesity and
`
`cachexia.
`
`Peripheral MCTR and MC3R can be pharmacalogically activated to induce anti-
`
`38
`
`inflammation. The endogenous agonist a-melanocyte—stimulating hormone (aMSH},
`
`like other protective mediators, is released by immune cells to counterbalance
`
`proinflammatory signals, thus preventing excessive tissue damade. In line with the
`
`resolution of inflammation concept, therapeutics targeting MC1R and MC3R act by
`
`mimicking the body's own protective resources and might be characterized by a lighter
`
`burden of side effects.
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`P4934 PC00/108725 G00055
`
`10
`
`Shown to be effective in rheumatic diseases since the early 1950s, the use of
`
`corticotropin or adrenocorticotropin hormone (ACTH) declined when synthetic
`
`glucocorticoids became available. However, the discovery of an alternative anti-
`
`inflammatory mechanism for ACTH involving activation of peripheral MC receptors on
`
`immune cells has revived the interest in developing novel ACTH-ike molecules with no
`
`steroidogenic effects for the treatment of joint diseases such as gout or RA (rheumatoid
`
`arthritis}. However, the limitation in the translational delivery of novel MC drugs besides
`
`the marketed ACTH formulations is imposed by the lack of receptor selectivity achieved
`
`10
`
`50 far.
`
`innovative approaches in G protein-coupled receptor drug discovery might helpto
`
`overcome this limitation. Allosteric modulation consists in the ability of a molecule to
`
`enhance (positive modulation} or reduce (negative modulation) the effect of the
`
`endogenous ligand by binding to a distinct site of the receptor protein, termed allasteric
`
`site. A higher degree of selectivity is expected as allosteric regions are less conserved
`
`among the five MCRs, and indeed, allosteric modulators at MC4R are currently under
`
`development for the treatment of obesity.
`
`Another ernerging concept of significant therapeutic interest is the one of biased
`
`agonism. The obsolete notion that receptors could exist in fvo unique canformations,
`
`the active one and the inactive one, has been replaced with the conception that
`
`muliple active conformations can exist, each one creating a distinct signal yielding
`
`multiple functional outcomes. Receptor activation, rather than linear and static, is
`
`emerging as a highly dynamic and multidimensional process in whicha diversity of
`
`active conformations may beinduced by different molecules leading to distinct effects.
`
`Fhe small molecule AP1189 (b)-N-trans-(3-[1-(2-nitrophenyl} 1 H-pyral-2-yl]-
`
`allylidene}-aminoguanidium acetate) has been characterized as a biased agonist at
`
`38
`
`receptors MC1R and MC3R, which does not induce canonical cAMP generation, but
`
`cause ERK 1/2 phosphorylation, a signaling responsible for the proefferocytic effect
`
`evoked in mouse orimary macrophages. AP1189 was shown to reduce cytokine
`
`release in macrophages, whereas no melanogenesis was induced by AP 1189 in
`
`melanocytes.
`
`in vivo, oral AP1189 elicits ant-inflammatory actions in peritonitis and
`
`accelerated the resctution phase, and afforded significant reduction of macroscopic
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`

`

`P4934 PC00/108725 G00055
`
`YW
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`and histological parameters of joint disruption in experimental inflammatory arthritis.
`
`AP1189is thus a biased dual agonist at MC1R and MC3R with anti-infammatory
`
`properties together with a lack of effect on melanogenesis.
`
`Melanocortin therapy by using adrenocorticotropic harmone (ACTH) or non-
`
`steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in
`
`experimental glomerular diseases and induces remission of nephrotic syndrome in
`
`patients with diverse giomerulopathies, even those resistant to steroids.
`
`10
`
`Proteinuria, the hallmark of glomerular injury, is a cammonfinding on urinalysis, and is
`
`by liself a strong, independent and modifiable risk factor for end stage renal disease,
`
`premature death of cardiovascular origin, and ischemic stroke in patients with diabetes.
`
`Despite recent advances refractory proteinuria continues to be a challengein clinical
`
`practice.
`
`itis an aspect of the present disclosure to provide a composition comprising a
`
`compound of formula (or dal:
`
`Ry
`
`Ry
`
`Rs
`
`20
`
`formula (1)
`
`

`

`P4934 PC00/108725 G00055
`
`t2
`
`Ry
`
`
`
`formula (la)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof:
`
`wherein
`
`nis 1,2 or3;
`
`30
`
`each Ry, Ro, Rs, Ry and Rs is independently selected from the group consisting of
`
`hydrogen, optionally substituted Cic-alkyl, optionally substituted Cas-cycioalkyl,
`
`optionally substituted Co.-alkenyl, optionally substituted C.c-alkadienyl, optionally
`
`substituted Czac- alkynyl, hydroxy, optionally substituted C.-c-alkoxy, aptionally
`
`substituted Ca.-alkenyioxy, carboxy, optionally substituted C;,-alkoxycarbonyl,
`
`optionally substituted Ci. alkylcarbony!, formyl, Cy.-alkylsulphonylamino, optionally
`
`substituted aryl, optionally substituted aryloxycarbony!, optionally substituted aryloxy,
`
`optionally substituted aryicarbonyl, optionally substituted arylamine,
`
`aryisuiphonylamino, optionally substituted heteroaryl, optionally substituted
`
`heteroaryioxycarbonyl, optionally substituted heteroaryloxy, optionally substituted
`
`heteroaryicarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamina,
`
`optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl,
`
`optionally substituted heterocyclyloxy, optionally substituted heterocyclyicarbony|,
`
`optionally substituted heterocyclylamino, heterocyclylsulphonylamine, amino, mono-
`
`

`

`P4934 PC00/108725 G00055
`
`43
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`and ci(C..-alkylamine, carbamoyl, mono- and di{C,.alkyaminocarbonyl, amino-Cy..-
`
`alky-aminocarbonyl, mono- and diCi.<- alkylamino-C,.-alky-aminocarbonyl, Cis-
`
`aikyicarbonylaming, aminc-C..<alkyl carbonylamino, mono- and d#C..alkylamino-C,
`
`s-alkyl-carbonylamino, cyano, guanidino, carbamido, C,.-alkanoyloxy, Cis-
`
`alkyisulphonyl, C.s-alkylsuiphinyl, C1s-alkylsulphonyl- oxy, aminosulfonyl, mono- and
`
`di{C..alkyiaminosulfony!, nitro, optionally substituted C,.-alkylthio and halogen,
`
`where any nitrogen-bound C,s-alkyl is optionally substituted with hydroxy, C..<-alkoxy,
`
`Crs5-alkenyloxy, amino, mono- and diC..alkylamino, carboxy, Cr.-
`
`aikyicarbonylamino, halogen, C..alkylthio, C.-c-alkyl-sulphonyl-amino or quanidine:
`
`10
`
`each Re and Re is independently selected from the aroup consisting of hydrogen,
`
`optionally substituted C.-s-alkyl, optionally substituted Cs-s-alkeny!, optionally
`
`substituted Cy,- alkacienyl, optionally substituted Cy-c-alkynyl, optionally substituted
`
`Cy-e-alkoxycarbonyl, optionally substituted C..-alkyicarbonyl, optionally substituted
`
`aryi, optionally substituted aryloxycarbonyi, optionally substituted aryicarbony|,
`
`optionally substitufed heteroaryl, optionally substituted heteroaryloxycarbony|,
`
`optionally substituted heteroarylcarbony!, aminocarbony!, mono- and di{Cy<-
`
`aikylaminocarbonyl, amino- C.<-alkyl-aminocarbonyl and mono- and difC..-
`
`alkyDamino- C,..-alkyl-aminocarbonyl, or Re and Rr may together form a five- or six-
`
`membered nitrogen-containing ring:
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatrnent of a kidney
`
`disease.
`
`itis also an aspect to provide use of a composition comprising a compound of formula
`
`€f or dak.
`
`

`

`P4934 PC00/108725 G00055
`
`14
`
`
`
`formula (}
`
`
`
`formula la}
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof: wherein each of n, R:, Ro, Rs, Ra and Rs, Re and
`
`R; are as defined herein above, or a pharmaceutically acceptable derivative thereof,
`
`for ihe manufacture of a medicament for the treatment of a kidney disease.
`
`10
`
`His also an aspect to provide a method for treating a kidney disease, said method
`
`comprising one or more steps of administration of a composition comprising a
`
`compound of formula () or dal:
`
`

`

`P4934 PC00/108725 G00055
`
`45
`
`Ry
`
`R.3
`
`uN
`
`Rg
`
`oe
`
`formula (}
`
`
`
`Ro
`
`Ra
`
`Ry
`
`Ry
`
`
`
`tX 2Lan iNY
`
`Rs
`
`HN
`
`\
`
`Ry
`
`5
`
`formula {la}
`
`incluciing tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof: wherein each of n, Ri, Ro, Rs, Ry and Rs, Rs and
`
`R; are as defined herein above, or a pharmaceuiically acceptable derivative thereof, to
`
`40
`
`an individual in need thereof.
`
`The present disclosure also provides 4 composition comprising a compound of formula
`
`ay:
`
`

`

`P4924 PC00/108725 G00055
`
`16
`
` NH»
`
`HoN
`
`formula (f)
`
`incluciing tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof, or a pharmaceutically acceptable derivative thereof,
`
`for use in the treatment of a kidney disease.
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`{fy (la) or CH as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease present with proteinuria.
`
`10
`
`Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine
`
`contains very ittle protein; an excess is suggestive of illness. The main mechanismsto
`
`cause proteinuria is disease in the kidney (esp. the glomerulus) or kidney damage,
`
`increased quantity of proteins in serum (overflow proteinuria}, low reabsorption at
`
`$5
`
`proximal tubule, certain biclogical agents and excessive fluid intake.
`
`Proteinuria may be defined as defined as >3.5 g per 1.73 m¥ body surface area per
`
`day. or > 40 mg per square meter body surface area per hour in children.
`
`20
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`(fy, (la) or CH as defined herein for use in the treatment of a kidney disease, wherein
`
`Said kidney disease present with proteinuria defined as >3.5 g per 1.73 m* body
`
`Surface area per day, or > 40 mg per square meter body surface area per hour in
`
`children.
`
`

`

`P4934 PC00/108725 G00055
`
`17
`
`A ‘kidney disease presenting withproteinuria’ means that proteinuria is an associated
`
`symptom or sign of said kidney disease. A ‘kidney disease presenting with proteinuria’
`
`may also be described as a kiciney disease associated with proteinuria or a kidney
`
`disease with proteinuria or a proteinuric kidney disease.
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`{h, (la) or CE) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is a glomerular disease, such as a disease affecting the podocytes
`
`of the glomerul:.
`
`10
`
`A glomerular disease may also reflect any type of glomerular injury caused by
`
`giornerular disease or any other stimuli, such as other underlying diseases or
`
`influences.
`
`The term ‘caused by’ a disease in the present context means that the injury arises or
`
`emerges as a cause or result of a disease, such as an underlying disease, i.e. as a
`
`result of the pathologic condition.
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`{B, (la) or CE) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is nephrotic syndrome (glomerulonephrosis).
`
`Nephrotic syndrome is a collection of symptoms due to kidney damage, including
`
`proteinuria, low blood albumin levels, high blood lipids, and significant swelling. Other
`
`symptoms may include weight gain, feeling tired, and foamy urine. Complications may
`
`include blood clots, infections, and high blood pressure. Causes include a number of
`
`Kidney diseases and may also occur as a complication of for example diabetes or
`
`lupus. The underlying mechanism typically involves damage to the glomeruli of the
`
`kidney.
`
`30
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`ify, (la) or GH} as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is primary nephrotic syndrome(primary glomerulonephrosis).
`
`

`

`P4934 PC00/108725 G00055
`
`18
`
`in one embodiment said primary nephrotic syndrome is membranous
`
`giorneruionephritis (MGN) (or membranous nephropathy (MN}).
`
`in one embodiment, fhe membranous nephropathyis idiopathic membranous
`
`nephropathy (MN).
`
`in one embodiment said primary nephrotic syndrome is focal segmental
`
`giomeruiosclerosis (FSGS)
`
`10
`
`in one embodiment said primary nephrotic syndrome is membranoproliferative
`
`giomeruionephritis (MPGN}) (mesangiccapilary giomerulonephritis}.
`
`in one embodiment said mermbranoproliferative glomerulonephritis (MPGN} is selected
`
`fram Type 1 MPGN and Type 2 MPGN.
`
`in one embodiment said primary nephrotic syndrome is rapidly progressive
`
`giomerulonephritis (RP-GN)} (crescentic GN}.
`
`in one embodiment said primary nephrotic syndrome is minimal change disease
`
`{MCD}.
`
`in one embodiment there is provided a composition comprising a compound of formula
`
`{B, (la) or CE) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is secondary nephrotic syndrome (secondary glomerulonephrasis}.
`
`in one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`disease (or simply caused by a disease}. The term ‘caused by’ a disease in the present
`
`context meansthat the nephrotic syndrome arises or emerges as a cause or result of a
`
`disease, such as an underlying disease, i.e. as a result of the pathologic condition.
`
`30
`
`in one embodiment said secondary nephrotic syndrame is caused by an underlying
`
`autoimmune disease.
`
`in one embodiment said secondary nephratic syndrame is caused by an underlying
`
`cancer disease.
`
`

`

`P4934 PC00/108725 G00055
`
`9
`
`in one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`genetic disorder.
`
`in one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`disease selected from the group consisting of: Systemic lupus erythematosus (SLE),
`
`Diabetic nephropathy, Sarcoidosis, Sjdgren's syndrome, Amyloicdasis, Multiple
`
`myeloma, Vasculitis, Cancer and Genetic disorders (such as congenital nephrotic
`
`syndrome}.
`
`10
`
`Lupus nephiitis is an inflammation of the kidneys caused by SLE. Hence, in one
`
`embodiment the secondary nephrotic syndrome is caused by lupus nephritis.
`
`in one embodiment said secondary nephrotic syndrame is caused by Diabetic
`
`nephropathy.
`
`in one embodiment said secondary nephratic syndrame is caused by an infectian.
`
`in one embodiment said secondary nephrotic syndrome is caused by a urinary tract
`
`infection.
`
`in one embodiment said secondary nephrotic syndrome is caused by an infection
`
`selected from the group consisting of HIV, syphilis, hepatitis such as hepatitis A, B and
`
`€, post-streptococcal infection, urinary schistosomiasis and Ebola.
`
`in one embodiment said secondary nephrotic syndrome is drug-induced; i.e. a drug-
`
`induced nephrotic syndrome.
`
`in one embodiment said drug-induced nephrotic syndrome is caused by a drug
`
`30
`
`selected from the group consisting of antibiotics, nonsteroidal anti-inflammatory drugs
`
`{NSAID}, radioconirasi media, anticancer drugs, antirheumatic drugs, antibody-based
`
`therapies, anti-TNF-a therapies, penicillamine, nicotine, lithium carbonate, gold and
`
`other heavy metals, ACE inhibitors and opiates (such as heroin).
`
`

`

`P4934 PC00/108725 G00055
`
`26
`
`Fhe term ‘caused by’ a drug in the present con