- TARGETED PLASMA PROTEIN DEGRADATION
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The present invention is directed to the bifunctional compounds and the use of such bifunctional compounds to lower plasma levels of extracellular target molecules by lysosomal degradation. Such bifunctional compounds have a cell surface receptor ligand covalently linked to a ligand that is capable of binding to an extracellular target molecule (such as a ligand for a growth factor, a cytokine, a chemokine, a hormone, a neurotransmitter, a capsid, a soluble receptor, an extracellular secreted protein, an antibody, a lipoprotein, an exosome, a virus, a cell, or a plasma membrane protein), where the cell surface receptor is associated with receptor mediated endocytosis, including asialoglycoprotein receptor (ASGPR) mediated lysosomal degradation and mannose-6-phosphate (M6PR) mediated lysosomal degradation. Pharmaceutical compositions comprising such bifunctional compounds and methods of treating a disease or disorder mediated by an extracellular molecule using such bifunctional compounds are also provided herein.
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- CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDERS
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The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.
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Paragraph 0624; 0627
(2020/06/16)
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- CYCLIC PENTAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDER
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The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I):, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein X1, R1, R2, R3, R4, R5, R6, R6', R7, R7', R8, R9, R9', R10, R11, R12, and n are described herein.
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- N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model
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Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
- Hoveyda, Hamid R.,Fraser, Graeme L.,Zoute, Ludivine,Dutheuil, Guillaume,Schils, Didier,Brantis, Cyrille,Lapin, Alexey,Parcq, Julien,Guitard, Sandra,Lenoir, Fran?ois,Bousmaqui, Mohamed El,Rorive, Sarah,Hospied, Sandrine,Blanc, Sébastien,Bernard, Jér?me,Ooms, Frédéric,McNelis, Joanne C.,Olefsky, Jerrold M.
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p. 5169 - 5180
(2018/10/02)
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- COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERS
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The present invention is directed to novel compounds of formula (I) and their use in treating metabolic diseases.
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Page/Page column 207-208
(2010/06/22)
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- Oxazinanones as chiral auxiliaries: Synthesis and evaluation in enolate alkylations and aldol reactions
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Homochiral β-amino esters (prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-Acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish α-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of (R)-N-propanoyl-4-iso- propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral α-methyl-β- hydroxy-carboxylic acids. The Royal Society of Chemistry 2006.
- Davies, Stephen G.,Garner, A. Christopher,Roberts, Paul M.,Smith, Andrew D.,Sweet, Miles J.,Thomson, James E.
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p. 2753 - 2768
(2008/02/10)
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- Matrix metalloprotease inhibitors
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Compounds of formula (I): STR1 as single stereoisomers or mixtures thereof and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as interstitial collagenases, and are useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteases, for example arthritic diseases or bone resorption disease, such as osteoporosis.
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- A new methodology for the synthesis of β-amino acids
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A differentially functionalized succinic acid unit 6 undergoes alkylation with excellent regio- and high stereocontrol at the carbon α to the imide to furnish the alkylated product 7 in 60-83% yield. Selective removal of the imide provides 8 in 80-90% yie
- Sibi, Mukund P.,Deshpande, Prasad K.
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p. 1461 - 1466
(2007/10/03)
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- A general method for the synthesis of enantiomerically pure β- substituted, β-amino acids through α-substituted succinic acid derivatives
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A general procedure for the synthesis of enantiopure β-substituted, β- amino acids is presented. Alkylation of the sodium enolates derived from chiral N-acyloxazolidinone imides 2 (R = Me, i-Pr, t-Bu, Ph, Bn) with tert- butyl bromoacetate afforded the 2-substituted succinate derivatives 3 in good yields (82-89%) and with high selectivity (≥ 93;7). Following hydrolysis, Curtius rearrangement of the resulting carboxylic acid provided the enantiopure benzyloxycarbonyl (Cbz)-protected β-amino esters 6 in good yields (74-79%).
- Evans, David A.,Wu, Leester D.,Wiener, John J. M.,Johnson, Jeffrey S.,Ripin, David H. B.,Tedrow, Jason S.
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p. 6411 - 6417
(2007/10/03)
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- Chemo-enzymatic synthesis of chiral 2-substituted succinic acid derivatives
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Prochiral discrimination by the biocatalyst Alcalase, an enzyme preparation of subtilisin Carlsberg, was used to effect enantio- and regioselective monohydrolysis of a variety of (RS)-2-substituted succinate diesters to afford the corresponding half esters in modest to excellent enantiomeric excesses (>99%). Exploitation of malonate chemistry, as well as recycling of the unhydrolyzed isomer from the enantioselective hydrolysis, has resulted in a process which is both practical and economical.
- Bailey, Murray D.,Halmos, Ted,Adamson, Dan,Bordeleau, Josee,Grand-Maitre, Chantal
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p. 3285 - 3295
(2007/10/03)
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- MATRIX METALLOPROTEASE INHIBITORS
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Compounds of formula (I): STR1 as single stereoisomers or mixtures thereof and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as interstitial collagenases, and are useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteases, for example arthritic diseases or bone resorption diseases, such as osteoporosis.
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- A concise asymmetric synthesis of the potent enkephalinase inihibitor kelatorphan
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A concise asymmetric synthesis of the enkephalinase inhibitor Kelatorphan has been completed in seven steps from commercially available hydrocinnamyl chloride. The synthesis features as a key step an asymmetric C-C bond formation which utilizes Oppolzer b
- Djuric
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p. 871 - 882
(2007/10/02)
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- RENIN INHIBIOTRS
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Renin inhibiting compounds containing a single α-amino acid of the formula: STR1 and analogs thereof which inhibit the substrate-cleaving acting or renin, pharmaceutical compositions containing these compounds, processes for producing the compounds and methods of treating hypertension which employ the novel renin inhibitors.
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- HETEROCYCLIC PEPTIDE RENIN INHIBITORS
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A renin inhibiting compound of the formula STR1 wherein X is N, O or CH; R 1 is absent or a functional group; A and L are independently selected from absent, C=O, SO 2 and CH 2 ; D is C=O, SO. sub.2 or CH 2 ; Y is N or CH; R 2 is hydrogen, loweralkyl or substituted alkyl; Z is a functional group; R 3 is loweralkyl or substituted alkyl; n is 0 or 1; and T is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.
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- Peptidyl difluorodiol renin inhibitors
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A renin inhibiting compound of the formula: wherein A is a functional group; W is (1)-C(O)-,(2)-CH(OH)-or(3)-N(R?)-wherein R? is hydrogen or loweralkyl; U is (1)-C(O)-,(2)-CH?-or(3)-N(R?)-wherein R? is hydrogen or lower alkyl, with the proviso that when W is-CH(OH)-then U is-CH?-and with the proviso that U is-C(O)-or-CH?-when W is-N(R?)-; V is (1)-CH-,(2)-C(OH)-or(3)-C(halogen)-with the proviso that v is-CH--when U is-N(R?)-; Q is-CH(R?)-or-C(=CHR1a)-wherein R? is (1) loweralkyl,(2) cycloalkylalkyl,(3) arylalkyl,(4) (heterocyclic) alkyl,(5) 1-benzyloxyethyl,(6) phenoxy,(7) thiophenoxy or(8) anilino, provided that B is-CH?-or-CH(OH)-or A is hydrogen when R? is phenoxy, thiophenoxy or anilino and R1a is aryl or heterocyclic; R? is a functional group; R? is (1) loweralkyl,(2) cycloalkylmethyl or(3) benzyl; R? is-CH(OH)-or-C(O)-; R? is-CH(OH)-or-C(O)-; and Z is (1) lower alkyl,(2) aryl,(3) arylalkyl,(4) cycloalkyl,(5) cycloalkylalkyl,(6) heterocyclic or(7) (heterocyclic)alkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof.
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- Renin-inhibiting functionalized peptidyl aminodiols and - triols
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A renin inhibiting compound of the formula: or a pharmaceutically acceptable salt, ester or prodrug thereof.
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- Renin-inhibiting peptidyl heterocycles
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A renin inhibiting compound of the formula:*(formula 01)* wherein A is a substituent; W is C=O, CHOH or NR2 wherein R2 is hydrogen or loweralkyl; U is C=O, CH2 or NR2 wherein R2 is hydrogen or loweralkyl, with the proviso that when W is CHOH then U is CH2 and with the proviso that U is C=O or CH2 when W is NR2; V is CH, C(OH) or C(halogen) with the proviso that V is CH when U is NR2; R1 is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (unsubstituted heterocyclic)methyl, (substituted heterocyclic)methyl, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B is CH2 or CHOH or A is hydrogen when R1 is phenoxy, thiophenoxy or anilino; R3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl,(alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzyl or heterocyclic ring substituted methyl; R4 is loweralkyl, cycloalkylmethyl or benzyl; R5 is OH or NH2; and Z is a substituent. Also disclosed are compositions for and a method of treating hypertension, methods of making the renin inhibiting compounds and intermediates useful in making the renin inhibiting compounds.
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