- Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and in Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model
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A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure-Activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
- Horatscheck, André,Andrijevic, Ana,Nchinda, Aloysius T.,Le Manach, Claire,Paquet, Tanya,Khonde, Lutete Peguy,Dam, Jean,Pawar, Kailash,Taylor, Dale,Lawrence, Nina,Brunschwig, Christel,Gibhard, Liezl,Njoroge, Mathew,Reader, Janette,Van Der Watt, Mari?tte,Wicht, Kathryn,De Sousa, Ana Carolina C.,Okombo, John,Maepa, Keletso,Egan, Timothy J.,Birkholtz, Lyn-Marie,Basarab, Gregory S.,Wittlin, Sergio,Fish, Paul V.,Street, Leslie J.,Duffy, James,Chibale, Kelly
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p. 13013 - 13030
(2020/11/13)
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- PHARMACEUTICAL COMPOUND, SALTS THEREOF, FORMULATIONS THEREOF, AND METHODS OF MAKING AND USING SAME
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Salts, hydrates and solvates of Compound I and methods of making and using the same and related dosage forms thereof are disclosed.
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- PHARMACOLOGICALLY ACTIVE IMIDAZO[4,5-C]PYRIDINES
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The invention relates to 6-substituted imidazo[4,5-c]pyridines of formula 1, in which X is O (oxygen) or NH and Y has either the meaning -CH2-AR or Y denotes the group gp (gp) wherein Z has the meaning -CHR8- or -CHR8-CHR9-. The compounds have gastric secretion inhibiting and excellent gastric and intestinal protective action properties.
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Page/Page column 42
(2010/02/11)
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- 2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization
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Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A2A antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes Asub
- Minetti, Patrizia,Tinti, Maria Ornella,Carminati, Paolo,Castorina, Massimo,Di Cesare, Maria Assunta,Di Serio, Stefano,Gallo, Grazia,Ghirardi, Orlando,Giorgi, Fabrizio,Giorgi, Luca,Piersanti, Giovanni,Bartoccini, Francesca,Tarzia, Giorgio
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p. 6887 - 6896
(2007/10/03)
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- 1,3-DIHYDROIMIDAZOLE FUSED-RING COMPOUND
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The objective of this invention is to provide novel compounds that show excellent DPPIV-inhibiting activity. The present invention provides compounds represented by the general formula (I), salts thereof, or hydrates thereof, [wherein,T1 stands for a monocyclic or bicyclic 4 to 12-membered heterocycle having 1 or 2 nitrogen atoms in the ring, which may have substituents; in formula (I), the following formula represents a double bond or a single bond; X3 denotes an oxygen atom or a sulfur atom; X1 denotes a C2-6 alkynyl group which may have substituents; Z1 denotes a nitrogen atom or the formula -CR3=; Z2 and Z3 each independently denote a nitrogen atom, the formula -CR1=, a carbonyl group, or the formula -NR2-; R1, R2, R3, and X2 each independently denote a C1-6 alkyl group which may have substituents, and such].
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Page/Page column 82
(2008/06/13)
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- IMIDAZOPYRIDINES AS MUSCARINIC AGENTS
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The compound of the formula: STR1 where R 1 is H, alkyl, perhaloalkyl, arylalkyl, alkenyl or alkynyl; R 2 is H when R. sub.4 is other than H, and, when R 4 is H, R 2 is STR2 in which R 5 is hydrogen or alkyl; R 3 is hydrogen or halogen; R. sub.4 is H or STR3 X, Y and Z are, independently, nitrogen or carbon, at least one of X, Y or Z being nitrogen; n is 1 or 2; n 1 is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof are centrally active muscarinic agents.
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- Gaba-agonistic imidazo(4,5-c)pyridines useful as pharmaceuticals
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Imidazo(4,5-c)pyridines of the formula STR1 wherein X is O, S or NH;Y is --NR 2 --CH N-- or --N CH--NR 2 --;R 1 is 1-benzothienylmethyl, naphthylmethyl, or benzyl which is mono- or di-substituted by F, Cl, NO 2, CF 3 or a combination thereof, and;R 2 is alkyl of 1-4 C atoms or cyclopropylmethyl,or a physiologically acceptable acid addition salt thereof,have valuable pharmacological activity, e.g., as GABA agonists.
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