- Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer's disease
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Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
- Helal, Christopher J.,Kang, Zhijun,Lucas, John C.,Gant, Thomas,Ahlijanian, Michael K.,Schachter, Joel B.,Richter, Karl E.G.,Cook, James M.,Menniti, Frank S.,Kelly, Kristin,Mente, Scot,Pandit, Jay,Hosea, Natalie
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supporting information; experimental part
p. 5703 - 5707
(2010/04/30)
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- Synthesis of imidazole intermediates
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The invention provides a method for synthesis of compounds of formula wherein R1 and R19 are as defined. Compounds of formula 12 are useful as intermediates for synthesizing compounds having pharmacological activity inhibiting cdk5, cdk2, and GSK-3.
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- Imidazole derivatives
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The invention provides compounds of formula 1 wherein R1, R2, R3, and R4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.
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