- An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders
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A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC50 = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.
- Porter, Jacob D.,Vivas, Oscar,Weaver, C. David,Alsafran, Abdulmohsen,DiMilo, Elliot,Arnold, Leggy A.,Dickson, Eamonn J.,Dockendorff, Chris
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supporting information
(2019/11/11)
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- COMPOUNDS AND METHODS FOR REGULATING INSULIN SECRETION
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Disclosed herein are methods for inducing insulin secretion in a glucose-dependent manner and compounds for use in these methods.
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Page/Page column 126; 127
(2018/10/19)
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- Novel HIV reverse transcriptase inhibitors
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The invention is related to compounds of Formula (I), (II), or (III): or a pharmaceutically acceptable salt, solvate, ester, and/or phosphonate thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.
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Page/Page column 107
(2008/06/13)
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- Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE5) for the treatment of sexual dysfunction
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Compounds of formulae (IA) and (IB) or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity, wherein R1 is C1 to C3 alkyl substituted with C3 to C6 cycloalkyl, CONR5R6 or a N-linked heterocyclic group; (CH2)nHet or (CH2)nAr; R2 is C1 to C6 alkyl; R3 is C1 to C6 alkyl optionally substituted with C1 to C4 alkoxy; R4 is SO2NR7R8; R5 and R6 are each independently selected from H and C1 to C4 alkyl optionally substituted with C1 to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group; R10 is H or C1 to C4 alkyl optionally substituted with OH, C1 to C4 alkoxy or CONH2; H is an optionally substituted C-linked 5- or 6-membered heterocyclic group; Ar is optionally substituted phenyl; and n is 0 or 1; are potent and selective cGMP PDE5 inhibitors useful in the treatment of, inter alia, male erectile dysfunction and female sexual dysfunction.
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Page column 50
(2010/02/06)
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- Inhibitors of protein isoprenyl transferases
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Compounds having the formula STR1or a pharmaceutically acceptable salt thereof wherein R 1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L 2 --, and (i) heterocyclic-L 2 --; R 2 is selected from STR2(b) --C(O)NH--CH(R 14)--C(O)OR 15, STR3(d) --C(O)NH--CH(R 14)--C(O)NHSO 2 R 16, (e) --C(O)NH--CH(R 14)-tetrazolyl, (f) --C(O)NH-heterocyclic, and (g) --C(O)NH--CH(R 14)--C(O)NR 17 R 18 ; R 3 is heterocyclic, aryl, substituted or unsubstituted cycloalkyl; R 4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L 1 is absent or is selected from (a) --L 4 --N(R 5)--L 5 --, (b) --L 4 --O--L 5 --, (c) --L 4 --S(O) n --L 5 -- (d) --L 4 --L 6 --C(W)--N(R 5)--L 5 --, (e) --L 4 --L 6 --S(O)m--N(R 5)--L 5 --, (f) --L 4 --N(R 5)--C(W)--L 7 --L 5 --, (g) --L 4 --N(R 5)--S(O) p --L 7 --L 5 --, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, and (j) optionally substituted alkynylene are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.
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