Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

• C3 glomerulopathy is a rare disease of the kidney (the prevalence of C3G is estimated at 2-3 per 1,000,000 people).
• C3G is characterized by deposition of the protein known as C3 (a component of the body’s complement system) in the filtration units (the glomeruli) of the kidney, indicating complement involvement in causing kidney damage.
• C3 glomerulopathy is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli.
• DDD dense deposit disease
• MPGN membranoproliferative glomerulonephritis
• C3GN C3 glomerulonephritis
• C3 glomerulopathy Patients with C3 glomerulopathy often have high proteinuria and progressive deterioration in renal function. There is no approved treatment for patients with C3 glomerulopathy, including C3GN. Without treatment, C3G invariably leads to kidney failure, and kidney transplant is frequently the only option. Even after transplantation, the new kidney will frequently fail due to recurrence of the disease. BRIEF SUMMARY OF THE INVENTION
• the present disclosure is directed to a method of treating a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a C5aR antagonist.
• the C5aR antagonist is a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the C5aR antagonist is a compound having the formula:
• Figure 1 represents the patient’s Estimated glomerular filtration rate (eGFR) before and after treatment with compound 1.
• Figure 2 represents the histopathological improvement following treatment with compound 1.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C 1 - 8 means one to eight carbons).
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like.
• alkenyl refers to an unsaturated alkyl group having one or more double bonds.
• alkynyl refers to an unsaturated alkyl group having one or more triple bonds.
• Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
• cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C 3-6 cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices.
• Cycloalkyl is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
• heterocycloalkyl refers to a cycloalkyl group that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• heterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ring system.
• Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4- dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like.
• a heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
• alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
• an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present disclosure.
• a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms.
• alkenylene and alkynylene refer to the unsaturated forms of “alkylene” having double or triple bonds, respectively.
• heteroatoms consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
• the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
• heteroalkenyl and “heteroalkynyl” by itself or in combination with another term, means, unless otherwise stated, an alkenyl group or alkynyl group, respectively, that contains the stated number of carbons and having from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
• heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
• alkylenedioxy, alkyleneamino, alkylenediamino, and the like are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached.
• a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
• halo or halogen
• by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• haloalkyl are meant to include monohaloalkyl and polyhaloalkyl.
• C 1 - 4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
• aryl groups include phenyl, naphthyl and biphenyl
• heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzo
• aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like).
• alkyl in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
• aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term “alkyl” and related aliphatic radicals is meant to refer to unsubstituted version, unless indicated to be substituted.
• R’, R” and R”’ each independently refer to hydrogen, unsubstituted C 1 - 8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1 - 8 alkyl, C 1 - 8 alkoxy or C 1 - 8 thioalkoxy groups, or unsubstituted aryl-C 1 - 4 alkyl groups.
• R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4- , 5-, 6-, or 7-membered ring.
• -NR’R is meant to include 1-pyrrolidinyl and 4- morpholinyl.
• substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
• Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR’- or a single bond, and r is an integer of from 1 to 3.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) t - , where s and t are independently integers of from 0 to 3, and X is -O-, -NR’-, -S-, -S(O)-, - S(O) 2 -, or -S(O) 2 NR’-.
• the substituent R’ in -NR’- and -S(O) 2 NR’- is selected from hydrogen or unsubstituted C 1 - 6 alkyl.
• heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
• ionic liquid refers to any liquid that contains mostly ions.
• ionic liquid refers to the salts whose melting point is relatively low (e.g., below 250 °C).
• ionic liquids include but are not limited to 1-butyl-3- methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium tetrafluoroborate, 1-octyl-3- methylimidazolium tetrafluoroborate, 1-nonyl-3-methylimidazolium tetrafluoroborate, 1-decyl- 3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium hexafluorophosphate and 1-hexyl-3-methylimidazolium bromide, and the like.
• treating encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms).
• Treatment methods provided herein include, in general, administration to a patient an effective amount of one or more compounds provided herein.
• Suitable patients include those patients suffering from or susceptible to ⁇ i.e., prophylactic treatment) a disorder or disease identified herein.
• Typical patients for treatment as described herein include mammals, particularly primates, especially humans.
• Other suitable patients include domesticated companion animals such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.
• pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
• Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
• Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
• the compounds described in the Embodiments below can be obtained according to methods described in WO 2010/075257, WO 2011/163640 and WO 2016/053890.
• the present disclosure is directed to a method of treating a human suffering from or susceptible to complement 3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ia):
• the compound has the formula (Ib):
• X 1 is selected from the group consisting of CH and CR 1 ;
• n is an integer of from 0 to 2;
• X 2 is selected from the group consisting of CH and CR 2 ; and the subscript m is an integer of from 0 to 2.
• the compound has the formula (Ic):
• X 1 is selected from the group consisting of CH and CR 1 ;
• n is an integer of from 0 to 2;
• X 2 is selected from the group consisting of CH and CR 2 ; and the subscript m is an integer of from 0 to 2.
• the compound has the formula (Id):
• the subscript p is an integer of from 0 to 3;
• X 1 is selected from the group consisting of CH and CR 1 ;
• n is an integer of from 0 to 2
• X 2 is selected from the group consisting of CH and CR 2
• the subscript m is an integer of from 0 to 2.
• the compound has the formula (Ie):
• the compound is selected from the group consisting of
• the compound is
• a method of slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl
• a method of reducing glomerular inflammation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• a method of reducing C3 deposits and/or C5b-9 deposits in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• the human suffers from complement 3 glomerulonephritis. In some embodiments, the human suffers from progressive complement 3 glomerulonephritis. In some embodiments, the human suffers from recurrent complement 3 glomerulonephritis after a renal transplant. In some embodiments, the human suffers from dense deposit disease. [0047] A method of clearing glomerular endocapillary proliferation in a human suffering from or susceptible to C3 glomerulopathy is provided comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl
• a method of reducing glomerular inflammatory macrophages in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl
• a method of reducing proteinuria in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt thereof,
• C 1 is phenyl optionally substituted with from 1 to 3 R 1 substituents;
• C 2 is phenyl optionally substituted with from 1 to 3 R 2 substituents;
• C 3 is selected from the group consisting of C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with from 1-3 R 3 substituents;
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• each R 3 is independently selected from the group consisting of
• X is hydrogen or CH 3 .
• the compound has the formula (Ie):
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• the human suffers from complement 3 glomerulonephritis. In some embodiments, the human suffers from progressive complement 3 glomerulonephritis. In some embodiments, the human suffers from recurrent complement 3 glomerulonephritis after a renal transplant. In some embodiments, the human suffers from dense deposit disease. In some embodiments, the human had refractory disease to immunosuppressive drugs. [0057] A method of treating a human suffering from or susceptible to complement 3 glomerulopathy is provided comprising administering to the human an effective amount of a compound having the formula (Ie), or a pharmaceutically acceptable salt thereof, wherein
• each R 1 is independently selected from the group consisting of
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalky
• each R 2 is independently selected from the group consisting of
• each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of:
• p 0, 1 or 2.
• each R 1 is independently selected from the group consisting of halogen, -CN, -R c , -NR a R b ,
• each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl and wherein the aliphatic and cyclic portions of R a , R b and R c are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R 1
• substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring;
• each R 2 is independently selected from the group consisting of halogen, -R f , and -OR d ; wherein each R d is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, each R f is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of R d and R f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups;
• each R 3 is independently selected from the group consisting of halogen, -R i , -CO 2 R g , -CONR g R h , -NR h C(O)R g , - NR h C(O) 2 R i , -NR g R h , -OR g , -X 4 -R j , -X 4 -NR g R h , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -NHR j and -NHCH 2 R j , wherein X 4 is a C 1-4 alkylene; each R g and R h is independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from
• each R 1 is independently selected from the group consisting of C 1-8 alkyl and C 1-8 haloalkyl; each R 2 is independently selected from the group consisting of halogen and C 1-8 alkyl;
• each R 3 is -NR g R h wherein each R g and R h is independently selected from hydrogen and C 3-6 cycloalkyl;
• each R 1 is independently selected from the group consisting of C 1-3 alkyl and C 1-3 haloalkyl; each R 2 is independently selected from the group consisting of halogen and C 1-3 alkyl;
• each R 3 is -NR g R h wherein each R g and R h is independently selected from hydrogen and C 4-6 cycloalkyl;
• the compound is selected from the group consisting of
• the compound is
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• the method comprises one or more of: slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in the human, reducing glomerular inflammation in the human, clearing glomerular endocapillary proliferation in the human, reducing glomerular inflammatory macrophages in the human, reducing proteinuria in the human, slowing down the progression of renal disease in the human, stopping the progression of renal disease in the human, delaying end stage renal disease in the human, improving renal histology in the human, decreasing proteinuria in the human, slowing the increase in proteinuria in the human.
• the improvements may be supported by kidney biopsy.
• a method of slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing glomerular inflammation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing glomerular inflammation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing C3 deposits and/or C5b-9deposits in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing C3 deposits and/or C5b-9 deposits in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of clearing glomerular endocapillary proliferation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of clearing glomerular endocapillary proliferation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing glomerular inflammatory macrophages in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing glomerular inflammatory macrophages in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing proteinuria in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• a method of reducing proteinuria in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula:
• the human suffers from complement 3 glomerulonephritis. In some embodiments, the human suffers from progressive complement 3 glomerulonephritis. In some embodiments, the human suffers from recurrent complement 3 glomerulonephritis after a renal transplant. In some embodiments, the human suffers from dense deposit disease. [0078] In some embodiments, the complement 3 glomerulopathy is refractory to treatment. In some embodiments, the complement 3 glomerulonephritis is refractory to other treatment. In some embodiments, the human has refractory disease to immunosuppressive drugs.
• the human has refractory disease to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. In some embodiments, the human has refractory disease to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and glucocorticosteroids. In some embodiments, the human shows improved health- related quality of life changes. In some embodiments, the health-related quality-of-life is based on Short Form-36 version 2 (SF-36 v2) or EuroQOL-5D-5L (EQ-5D-5L) assessment.
• SF-36 v2 Short Form-36 version 2
• EQ-5D-5L EuroQOL-5D-5L
• the health-related quality-of-life is based on Short Form-36 version 2 (SF-36 v2) assessment. In some embodiments, the health-related quality-of-life is based on EuroQOL-5D- 5L (EQ-5D-5L) assessment. [0079] In some embodiments, the compound is administered twice daily. In some embodiments,
• the compound is administered once a day. In some embodiments, the compound is administered every other day. In some embodiments, the compound is administered every 3 days. In some embodiments, the compound is administered 3 times per day. In some
• the compound is administered 4 times per day.
• the human receives 30 mg of the compound daily. In some embodiments, the human receives 20 mg of the compound daily. In some embodiments, the human receives 10 mg of the compound daily. In some embodiments, the human receives 40 mg of the compound daily. In some embodiments, the human receives 60 mg of the compound daily. In some embodiments, the human receives 50 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg or 200 mg of the compound daily. [0081] In some embodiments, the human receives 30 mg of the compound twice daily. In some embodiments, the human receives 20 mg of the compound twice daily. In some embodiments, the human receives 10 mg of the compound twice daily. [0082] In some embodiments, the compound is administered orally. [0083] In some embodiments, the human has a Complement factor H related protein 5
• the human receives treatment for 12 weeks. In some embodiments, the human receives treatment for 12 weeks. In some embodiments, the human receives treatment for 12 weeks.
• the human receives treatment for 26 weeks. In some embodiments, the human receives treatment for 52 weeks. In some embodiments, the human receives chronic treatment. In some embodiments, the human receives continuous treatment. [0085] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is administered sequentially or concurrently in the same composition or not. [0086] In some embodiments, the one or more additional therapeutic agents is selected from immunosuppressive drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type- 1 receptor blockers (ARBs) and corticosteroids.
• ACE angiotensin-converting enzyme
• ARBs angiotensin II type- 1 receptor blockers
• the one or more additional therapeutic agents is selected from the group consisting of cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, tacrolimus, belimumab, OMS721, ACH-4471, AMY-101, Acthar Gel, SAND-5, corticotropin, CDX-1135, ramipril, perindopril, lisinopril, perindopril arginine, captopril, spirapril, quinapril, enalapril, imidapril, fosinopril, zofenopril, benazepril, trandolapril, verapamil, benazepril, amlodipine, trandolapril, P-003, cilazapril, delapril, moexipril, quinapril, fosinopril, tem
• the one or more additional therapeutic agents is selected from the group consisting of cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, and tacrolimus. [0088] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of corticosteroids, steroids, immunosuppressants, Immunoglobulin G agonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte function antigen-3 receptor
• Interleukin-2 ligands Interleukin-1 beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsin stimulators, Cannabinoid receptor antagonists, Histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors, Hemoglobin modulators, TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulin agonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosine kinase inhibitors,
• Immunoglobulin gamma Fc receptor IIB antagonists Immunoglobulin gamma Fc receptor IIB antagonists, T-cell antigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinase stimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17
• TLR-2 antagonists TLR-2 antagonists, complement factor D inhibitors, complement factor B inhibitors, complement C5 inhibitors, MASP-2 inhibitors, MASP-3 inhibitors,C3 inhibitors, pegylated APL-1, C1s inhibitors, C6 inhibitors, and T cell receptor antagonists.
• the one or more additional therapeutic agents is selected from the group consisting of obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, beclomethasone, betamethasone, betamethasone, betamet
• Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
• Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.
• the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
• isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
• radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
• isotopically- labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and compound 1 for example, those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.
• Isotopically-labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and compound 1 can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
• the methods, compositions, kits and articles of manufacture provided herein use or include compounds (e.g., (I), (Ia), (Ib), (Ic), (Id), (Ie) and compound 1) or pharmaceutically acceptable salts, prodrugs, or solvates thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule.
• the deuterium atom is a non-radioactive isotope of the hydrogen atom.
• Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of compounds or pharmaceutically acceptable salts, prodrugs, or solvates thereof, when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984).
• Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
• Treatment methods provided herein include, in general, administration to a patient an effective amount of the compounds provided herein.
• Suitable patients include those patients suffering from or susceptible to (i.e., prophylactic treatment) C3 glomerulonephritis.
• treatment methods provided herein comprise administering to a patient an effective amount of a compound provided herein.
• the compound(s) of the disclosure are preferably administered to a patient (e.g., a human) orally or topically.
• the compound(s) of the disclosure are administered to a patient (e.g., a human) systemically (intravenously or subcutaneously).
• the effective amount may be an amount sufficient to modulate C5a receptor activity and/or an amount sufficient to reduce or alleviate the symptoms presented by the patient.
• the amount administered is sufficient to yield a plasma concentration of the compound (or its active metabolite, if the compound is a pro-drug) high enough to detectably inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro.
• Treatment regimens may vary depending on the compound used and the particular condition to be treated; for treatment of most disorders, a frequency of administration of 4 times daily or less is preferred. In general, a dosage regimen of 2 times daily is more preferred, with once a day dosing particularly preferred.
• the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient) and the severity of the particular disease undergoing therapy, as well as the judgment of the prescribing medical practitioner. In general, the use of the minimum dose sufficient to provide effective therapy is preferred.
• Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.
• Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment or preventions of conditions involving pathogenic C5a activity (about 0.5 mg to about 7 g per human patient per day).
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
• a dosage regimen of 4 times daily, three times daily, or less is preferred, with a dosage regimen of once daily or 2 times daily being particularly preferred.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the prescribing medical practitioner.
• PHARMACEUTICAL COMPOSITIONS [0100]
• the compounds provided herein can be administered as compositions which will typically contain a pharmaceutical carrier or diluent.
• composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutical composition further comprises one or more additional therapeutic agents.
• the pharmaceutical compositions for the administration of the compounds of this disclosure may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
• the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
• the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifications as described in U.S.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, polyethylene glycol (PEG) of various average sizes (e.g., PEG400,
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin,
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the disclosure may also be in the form of oil-in- water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the compounds of the present disclosure may also be administered in the form of suppositories for rectal administration of the drug.
• compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials include cocoa butter and polyethylene glycols.
• the compounds can be administered via ocular delivery by means of solutions or ointments.
• transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
• creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present disclosure are employed.
• topical application is also meant to include the use of mouth washes and gargles.
• the compounds of this disclosure may also be coupled a carrier that is a suitable polymers as targetable drug carriers.
• suitable polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds of the disclosure may be coupled to a carrier that is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
• Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
• kits comprising, in one or more suitable containers, one or more pharmaceutical compositions and instructions for their use.
• kits comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), or compound 1, or a pharmaceutically acceptable salt thereof, and instructions for its administration are provided.
• kits comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), or compound 1, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and instructions for their administration are provided.
• the compounds of this disclosure are formulated into
• administration units which are packaged in a single packaging.
• the single packaging
• the compounds of this disclosure and optionally additional therapeutic agents are formulated into administration units and every single administration unit is individually packaged in a single packaging. Such individually packaged units may contain the
• composition in any form including but not limited to liquid form, solid form, powder form, granulate form, an effervescent powder or tablet, hard or soft capsules, emulsions, suspensions, syrup, suppositories, tablet, troches, lozenges, solution, buccal patch, thin film, oral gel, chewable tablet, chewing gum, and single-use syringes.
• Such individually packaged units may be combined in a package made of one or more of paper, cardboard, paperboard, metal foil and plastic foil, for example a blister pack.
• One or more administration units may be
• One or more administration units may be administered once or several times a day.
• One or more administration units may be administered three times a day.
• One or more administration units may be administered twice a day.
• One or more administration units may be administered on a first day and one or more administration units may be administered on the following days.
• Compound 1 has the formula: .
• EXAMPLES Example 1: study of compound 1 in a patient with progressive complement 3
• Proteinuria dropped approximately 80% with compound 1 treatment.
• Figure 2 represents the histopathological improvement following treatment with compound 1.
• H&E Haemotoxylin and Eosin staining before treatment with compound 1 demonstrates fibrinoid necrosis and multiple inflammatory cells.
• C Periodic acid-Schiff (PAS) staining after treatment with compound 1 shows a reduction in endocapillary hypercellularity and glomerular inflammation.
• B CD68 staining before treatment with compound 1.
• D CD68 staining after treatment with compound 1 demonstrates a reduction in glomerular macrophages. Protocol of the study:
• the primary safety objective of this study is to evaluate the safety and tolerability of compound 1.
• the primary efficacy objective is to evaluate the efficacy of compound 1 based on change from baseline in eGFR (MDRD, Estimated Glomerular Filtration Rate) and proteinuria.
• the secondary objectives of this study include assessment of: 1. Change from baseline in pharmacodynamic markers in plasma and urine, e.g., MCP-1, C3a, C5a, properdin, and sC5b-9; 2. Change from baseline in glomerular pathology based on renal biopsy; 3. Evaluation of the plasma concentrations of compound 1in C3 glomerulonephritis.
• the patient On Day 1, the patient will start compound 1 treatment. Patients will take compound 1 30 mg orally twice daily for an initial period of 84 days. The patient will visit the study center on Days 1, 8, 15, 29, 57, and 85. The compound 1 dose will be taken in the morning optimally within one hour after breakfast and in the evening optimally within one hour after dinner. If the patient’s clinical condition stabilizes or improves, and there are no adverse events preventing further treatment, the patient may be treated for another 84-day treatment cycle. The 84-day cycles may be repeated for a total of up to 4 cycles under this protocol. For the 84-day cycles after the first cycle, the patient will visit the study center every 4 weeks. There will be 4-week follow-up period after the patient stops the compound 1 treatment.
• Adequate contraception is defined as resulting in a failure rate of less than 1% per year (combined estrogen and progestogen [oral, intravaginal, or transdermal], or progestogen-only hormonal contraception (oral, injectable, or implantable), intra-uterine device, intra-uterine hormone releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence);
• the patient will be screened within a period not to exceed 21 days prior to Day 1.
• the compound 1 treatment period is at least 84 days and up to 336 days, and the patient will be followed for 4 weeks (28 days) after dosing is stopped.
• any adverse events that are deemed study drug-related and are ongoing at discharge will be followed-up to resolution or until a determination is made that the unresolved event is stable.
• the patient’s condition will be evaluated by the Investigator at the end of the study and appropriate standard of care medical treatment will be provided as needed. Safety Assessments
• Safety assessments include adverse events, physical examination abnormalities, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and urinalysis). Efficacy Assessments
• Efficacy assessments include: 1. First morning urinary PCR;
• Plasma and urine pharmacodynamic markers e.g., MCP-1, C3a, C5a, properdin, and sC5b-9;
• Glomerular inflammation e.g., crescents, inflammatory cell infiltrate, endocapillary proliferation
• C3 deposition in a follow-up renal biopsy sample e.g., crescents, inflammatory cell infiltrate, endocapillary proliferation
• Plasma samples will be collected on Day 1 (pre-dose), and Days 8, 15, 29, 57, and 85 for pharmacodynamic marker measurements, including, for example, complement fragments, and inflammatory cytokine and chemokine levels.
• Urine samples will also be collected on Day 1 (pre-dose) and Days 8, 15, 29, 57, and 85 for biomarker assessments including, for example, MCP-1, complement fragments, and inflammatory chemokine and cytokine levels.
• Plasma and urine samples will continue to be collected every 4 weeks during any subsequent 84-day cycles. Renal Histology
• Renal biopsies will be analyzed by periodic acid–Schiff (PAS) staining
• Demographics and Baseline Characteristics All patient baseline characteristics and demographic data (age, sex, race, ethnicity, weight, height, body mass index, smoking status, viral test results, C3 GN disease duration (from time of first diagnosis based on renal biopsy), renal transplant history, eGFR, proteinuria (PCR), urinary MCP-1:creatinine ratio, physical examination abnormalities, medical history, previous (within 6 months of screening) and concomitant medications (including other treatments for C3 GN) at study entry will be listed. Safety Analysis
• the primary safety endpoint is the patient incidence of adverse events.
• Other safety endpoints include: 1. Change from baseline in all safety laboratory parameters;
• the primary efficacy endpoints are the change from baseline over the treatment period in eGFR and first morning urinary PCR.
• Other efficacy endpoints include: 1. The percent change from baseline in plasma and urinary biomarkers, e.g., MCP-1, C3a, C5a, properdin, and sC5b-9; 2. Change from baseline to follow-up biopsy in glomerular inflammation (crescents, inflammatory cell infiltrate, and endocapillary proliferation), C3 deposits, and C5b-9 deposits.
• Plasma samples will be collected on Days 8, 15, 29, 57, and 85 to determine the plasma concentrations of compound 1 (and metabolites). Plasma concentrations of compound 1 will be listed and plotted by study visit.
• Example 2 A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of compound 1 in Patients with C3 Glomerulopathy
• the aim of this study is to evaluate the effect of compound 1 treatment on renal disease activity in patients with complement 3 glomerulopathy (C3G).
• C3G complement 3 glomerulopathy
• the intent is to slow down or improve renal disease with compound 1 treatment in these patients.
• the primary objective is to evaluate the efficacy of compound 1 compared to placebo based on histologic changes in C3G pathology from kidney biopsies taken before and during treatment.
• the secondary objectives of this study include assessment of: 1. The safety of compound 1 compared to placebo based on the incidence of adverse events, changes in clinical laboratory measurements, and vital signs;
• Patients will then be randomized, 1:1, to receive 30 mg compound 1 twice daily or matching placebo for 26 weeks in a double-blind, placebo-controlled manner. The 26-week double-blind period will be followed by a 26-week period during which all patients will receive compound 1 treatment.
• Patients will be screened for enrollment based on biopsy proven C3 glomerulopathy (i.e., 2-levels of magnitude greater staining of C3 than any combination of IgG, IgM, IgA, and C1q) and evidence of inflammation based on leukocyte infiltration and/or endocapillary proliferation.
• the screening period will be up to 28 days.
• Screening procedures will include written informed consent, demographics, medical history, medication history, physical examination and vital signs, 12-lead ECG, serum pregnancy test for women of childbearing potential, serum chemistry (including serum creatinine), hematology, urinalysis, urinary protein:creatinine ratio (PCR), viral and TB screening. If a patient did not have a renal biopsy in the past 12 weeks, a renal biopsy needs to be done prior to dosing. Prior to starting study drug treatment, blood samples will be collected for the following measurements to create a baseline profile for all patients: 1. C3, C3d, C3c, C3adesArg, and C4;
• Patients meeting inclusion criteria will start study drug treatment on Day 1. Patients will take compound 130 mg or matching placebo orally twice daily. The treatment period is 52 weeks (364 days). The study drug will be taken in the morning preferably with food and in the evening preferably with food, approximately 12 hours after the morning dose. Patients who receive placebo during the first 26 weeks, will receive compound 1 in a blinded cross-over. After the 364-day treatment period, all patients will be followed for 8 weeks (56 days) without study drug treatment. [0163] At post-Day 1 study visits, blood and urine samples will be collected for safety, efficacy, and pharmacokinetic and biomarker measurements.
• a serum pregnancy test for women of childbearing potential will be done regularly during the 52-week treatment period and at the end of the 8-week follow-up period. Physical examinations and vital signs assessments will be performed throughout the study. Health-related quality of life using the EQ-5D-5L and SF-36 v2 surveys will be assessed periodically over the course of the study. Study drug will be dispensed and drug accountability will be done. Concomitant medication and adverse event assessments will be made at every study visit. A follow-up renal biopsy will be performed at the following time points: 1. After the 26-week placebo-controlled treatment period;
• the dose(s) of concomitant immunosuppressive treatment may not be increased during the study. Treatment with these other drugs may be reduced or stopped during the study, if the patient’s condition justifies it. No new treatments may be added during the study period (active treatment period or follow up), unless the patient’s condition deteriorates to the extent that the investigator deems it in the best interest of the patient to do so. This will be considered a treatment failure.
• compound 1 or placebo dosing will initially be given based on the body weight at screening and the dose will be adjusted based on compound 1 plasma levels as shown in the table below.
• blood samples will be taken pre-dosing and at Hours 0.5, 1, 2, 3, 4, and 6 after the first compound 1 dose on Day 1 and plasma samples will be sent to the central laboratory for expeditious measurement of compound 1 and its metabolite in these patients. Dose adjustments will be made based on AUC 0-6 as shown in the table below.
• AUC 0-6 thresholds are based on the mean compound 1 plasma exposure (525 ng•hr/mL) and one standard deviation (174 ng•hr/mL) above or below the mean in adult patients from Phase 2 study CL002_168 in AAV.
• Adequate contraception is defined as resulting in a failure rate of less than 1% per year (combined estrogen and progestogen [oral, intravaginal, or transdermal], or progestogen-only hormonal contraception (oral, injectable, or implantable), intra-uterine device, intra-uterine hormone releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence);
• Secondary C3 disease e.g., infection-associated disease, or associated with another systemic or autoimmune disease;
• tuberculosis based on interferon ⁇ release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography done at screening or within 6 weeks prior to screening;
• IGRA interferon ⁇ release assay
• PPD tuberculin purified protein derivative
• Safety assessments include adverse events, physical examination abnormalities, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and urinalysis). Efficacy Assessments
• Efficacy assessments include: 1. Renal histology to determine the C3G Histologic Index (CHI) for disease activity and
• eGFR calculated by the Modification of Diet in Renal Disease (MDRD) equation from serum creatinine
• Plasma/serum samples will be collected according to the Time and Events Table for pharmacodynamic marker measurements, including, for example, complement fragments, and inflammatory cytokine and chemokine levels.
• Urine samples will also be collected according to the Time and Events Table for biomarker assessments including, for example, complement fragments, sCD163, and inflammatory chemokine and cytokine levels. Renal Histology
• renal biopsy samples will be assessed by:
• the primary efficacy endpoint is the percent change from baseline to week 26 in the C3G Histologic Index (CHI) for disease activity.
• the compound 1 and placebo groups will be compared by ANCOVA with treatment group and randomization strata (C3GN or DDD, and renal transplant or not) as factors, and baseline as covariate. Point estimates and corresponding 95% confidence intervals will be estimated for the difference between the compound 1 and placebo control group.
• the placebo group Since the placebo group will receive compound 1 during the second 26 weeks of the study, the change from Week 26 to Week 52 in the CHI in the placebo control group will be compared to the change from baseline to Week 26 in this group. This analysis will be done by the paired t-test.
• Point estimates and corresponding 95% confidence intervals will be estimated for the difference between the second 26 weeks (compound 1 treatment) and the first 26 weeks (placebo treatment).
• the change from baseline to Week 52 in the CHI will also be compared to the change from baseline with Week 26 in placebo control group using similar methodology as described for the primary efficacy endpoint.
• Other efficacy endpoints include:
• Continuous variables including eGFR, urinary PCR, urinary MCP-1:creatinine ratio, EQ-5D-5L, and SF-36 v2 will be analyzed using a mixed effects model for repeated measures (MMRM) with treatment group, visit, treatment-by-visit interaction, and randomization strata (C3GN or DDD, and renal transplant or not) as factors, and baseline as covariate. Patients will be considered as repeated measure units over visits. Point estimates and corresponding 95% confidence intervals will be estimated for the difference between the compound 1 group and the control group across 26 weeks using simple contrast from the model. Similar to the primary endpoint, the second 26 weeks will be compared to the first 26 weeks for the placebo group.
• MMRM mixed effects model for repeated measures
• Safety endpoints include: 1. Patient incidence of treatment-emergent serious adverse events, adverse events, and withdrawals due to adverse events;
• Laboratory data (actual values and change from baseline) will be listed by treatment group, patient, and study visit. Abnormal laboratory values will be flagged. Laboratory data will also be summarized by treatment group and study visit. Shift tables will be generated for shifts in laboratory parameters by study visit. Pharmacokinetic and pharmacodynamic marker analysis
• Plasma samples will be collected over the course of the study to determine the PK profile of compound 1 (and metabolites). Individual plasma concentrations of compound 1 (and metabolites) will be listed, plotted, and summarized descriptively and graphically. PK parameters will be calculated based on plasma compound 1 concentrations at the time of sample collection in relation to time of administration of the most recent dose of study medication. PK parameters of significant metabolites may also be calculated. [0202] Plasma and urinary PD markers will be summarized and may be analyzed using methods analogous to the efficacy parameters. The following parameters will be determined, where possible, in 12-17 year old patients:
• AUC 0-6 Area under the plasma concentration-time curve from Time 0 to Hour 6 on Day 1 Cmin Trough level plasma concentrations at post-Day 1 visits
• PK parameters and renal function based on eGFR will be evaluated.
• the data may also be used to evaluate the PK/PD relationship of compound 1 treatment.
• the change and/or percent change from baseline in urinary PCR, eGFR, urinary MCP-1:creatinine ratio, and other biomarkers may be used as PD markers.

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