22016-02-0Relevant articles and documents
Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors
Liu, Li,Tang, Manshu,Pragani, Rajan,Whitby, Frank G.,Zhang, Ya-Qin,Balakrishnan, Bijina,Fang, Yuhong,Karavadhi, Surendra,Tao, Dingyin,LeClair, Christopher A.,Hall, Matthew D.,Marugan, Juan J.,Boxer, Matthew,Shen, Min,Hill, Christopher P.,Lai, Kent,Patnaik, Samarjit
, p. 13551 - 13571 (2021/09/28)
Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC50 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.
4-isoxazolecarboxamide derivatives
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, (2008/06/13)
This invention is directed to compounds of the formula (I): STR1 wherein R1 is --OR4 (where R4 is hydrogen, lower alkyl, lower hydroxyalkyl, phenyl, phenyl-lower-alkyl, or --(CH2)n Y where n is an integer from 1 to 4 and Y is morpholino, -SR5, --C(O)OR5, --C(O)N(R6)2, --N(R6)2, or --N+ (R6)3 X-, in which R5 is lower alkyl, each R6 is independently selected from hydrogen or lower alkyl, and X is halogen) or --SR7 (where R7 is lower alkyl, phenyl-lower-alkyl, or --(CH2)n W where W is --N(R6)2 or --N+ (R6)3 X-, and n, R6 and X are as previously defined); R2 is lower alkyl, phenyl or phenyl-lower-alkyl; R3 is halo, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or --C(O)OR5 where R5 is as previously defined; and Z is a bond, 2,5-thienyl or 2,5-furanyl; or a pharmaceutically acceptable salt thereof. These compounds are useful in treating inflammation, autoimmune disease or allograft rejection in mammals.
Synthesis of New Anilidopyrimidinethione Derivatives
Khalil, Zarif H.,Yanni, Amal S.
, p. 494 - 497 (2007/10/02)
Interaction of acetoacetanilide (Ia) or its hydroxy derivative (Ib) with aromatic or heterocyclic aldehydes gave the corresponding α, β unsaturated ketones (II).The reaction of alcoholic solution of (II) with thiourea in a basic catalyst gave the corresponding pyrimidinethione derivatives (III).Fusion of (III) with amines, active methylene, and methyl compounds gave the corresponding condensation products IV, V, and VI.
Synthesis of New Anilido-Pyrazoline and Isoxazoline Derivatives
Khali, Zarif A.,Yanni, Amal S.
, p. 168 - 170 (2007/10/02)
Interaction of acetoacetanilide(Ia) or its hydroxy derivative(Ib) with aromatic (or heterocyclic) aldehydes gave the corresponding α,β-unsaturated ketones(II).The reaction of alcoholic solution of (II) with hydrazine hydrate or hydroxylamine in a basic ca
