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S├ębastien L Degorce, Scott Boyd, Jon O Curwen, Richard Ducray, Christopher T Halsall, Clifford D Jones, Franck Lach, Eva M Lenz, Martin Pass, Sarah Pass, Catherine Trigwell
Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R...
May 26, 2016: Journal of Medicinal Chemistry
Ashraf Saeed, Grant M Vaught, Kostas Gavardinas, Donald Matthews, Jonathan E Green, Pablo Garcia Losada, Heather A Bullock, Nathan A Calvert, Nita J Patel, Stephanie A Sweetana, Venkatesh Krishnan, Judith W Henck, John G Luz, Yong Wang, Prabhakar Jadhav
A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting...
January 28, 2016: Journal of Medicinal Chemistry
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