- Identification of RO4597014, a glucokinase activator studied in the clinic for the treatment of type 2 diabetes
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To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.
- Qian, Yimin,Corbett, Wendy L.,Berthel, Steven J.,Choi, Duk Soon,Dvorozniak, Mark T.,Geng, Wanping,Gillespie, Paul,Guertin, Kevin R.,Haynes, Nancy-Ellen,Kester, Robert F.,Mennona, Francis A.,Moore, David,Racha, Jagdish,Radinov, Roumen,Sarabu, Ramakanth,Scott, Nathan R.,Grimsby, Joseph,Mallalieu, Navita L.
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p. 414 - 418
(2013/07/25)
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- Highly efficient one-pot amination of carboxylate-substituted nitrogen-containing heteroaryl chlorides via Staudinger reaction
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An efficient one-pot method for the synthesis of tert-butyl 6-aminonicotinate (5) is described. The key transformation involves displacement of the chloro group in tert-butyl 6-chloronicotinate (2) with azide followed by a Staudinger reaction. The scope of this methodology is further extended for the synthesis of a series of carboxylate-substituted heteroaryl amines. In particular, we synthesized tert-butyl carboxylate-substituted amino-pyridine, -pyridazine, and -pyrazine. In addition to one-pot conversion, short reaction time, simplicity of operation, ease of purification, and good yields are the key advantages of this methodology.
- Kandalkar, Sachin R.,Kaduskar, Rahul D.,Ramaiah, Parimi Atchuta,Barawkar, Dinesh A.,Bhuniya, Debnath,Deshpande, Anil M.
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supporting information
p. 414 - 418
(2013/02/23)
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- 2-AMINOPYRIDIN-4-ONE AND 2-AMINOPYRIDINE DERIVATIVE BOTH HAVING BACE1-INHIBITING ACTIVITY
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The present invention provides a compound which has an effect of inhibiting amyloid-β production and is useful as a therapeutic agent for diseases induced by production, secretion and/or deposition of amyloid-β proteins. The present invention relates to a
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Page/Page column 184
(2011/09/15)
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- AMINODIHYDROTHIAZINE DERIVATIVES SUBSTITUTED WITH CYCLIC GROUPS
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This invention provides a compound of the formula (I): wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R1 is optionally substituted lower alkyl, optionally substituted lower alk
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Page/Page column 45-46
(2010/02/17)
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- 5-SUBSTITUTED-PYRAZINE OR PYRIDINE GLUCOKINASE ACTIVATORS
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The present invention provides a compound according to formula (I) where the substituent designations are provided in the specification. Pharmaceutical compositions comprising a compound according to formula (I) are also provided, said compounds being glucokinase activators which are useful in the treatment of type II diabetes.
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