- Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 2: Isoindoline containing inhibitors
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To obtain selective and potent inhibitors of dipeptidyl peptidases 8 and 9, we synthesized a series of substituted isoindolines as modified analogs of allo-Ile-isoindoline, the reference DPP8/9 inhibitor. The influence of phenyl substituents and different P2 residues on the inhibitors' affinity toward other DPPs and more specifically, their potential to discriminate between DPP8 and DPP9 will be discussed. Within this series compound 8j was shown to be a potent and selective inhibitor of DPP8/9 with low activity toward DPP II.
- Van Goethem, Sebastiaan,Van der Veken, Pieter,Dubois, Veronique,Soroka, Anna,Lambeir, Anne-Marie,Chen, Xin,Haemers, Achiel,Scharpe, Simon,De Meester, Ingrid,Augustyns, Koen
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scheme or table
p. 4159 - 4162
(2009/05/07)
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- Substituted pyrrolidine-2,4-dicarboxylic acid amides as potent dipeptidyl peptidase IV inhibitors
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A series of substituted pyrrolidine-2,4-dicarboxylic acid amides were synthesized as potential antidiabetic agents, and many of them showed good in vitro DPP-IV inhibition (IC50 = 2-250 nM) with selectivity over DPP-II, DPP8, and FAP enzymes. Selected compounds 8c and 11a showed in vivo plasma DPP-IV inhibition after oral administration in Wistar rats.
- Tsai, Ting-Yueh,Coumar, Mohane Selvaraj,Hsu, Tsu,Hsieh, Hsing-Pang,Chien, Chia-Hui,Chen, Chiung-Tong,Chang, Chung-Nien,Lo, Yu-Kang,Wu, Ssu-Hui,Huang, Chung-Yu,Huang, Yu-Wen,Wang, Min-Hsien,Wu, Hsin-Yi,Lee, Hong-Jen,Chen, Xin,Chao, Yu-Sheng,Jiaang, Weir-Torn
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p. 3268 - 3272
(2007/10/03)
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- COMPOUND INHIBITING DIPEPTIDYL PEPTIDASE IV
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The invention aims to provide a dipeptidyl peptidase IV inhibitor which is satisfactory in respect of activity, stability and safety and has an excellent action as a pharmaceutical agent. The invention is directed to a compound represented by the following general formula or a pharmaceutically acceptable salt thereof: wherein R1 and R2 each represents hydrogen, an optionally substituted C1-6 alkyl group, or -COOR5 whereupon R5 represents hydrogen or an optionally substituted C1-6 alkyl group, or R1 and R2, together with a carbon atom to which they are bound, represent a 3- to 6-membered cycloalkyl group, R3 represents hydrogen or an optionally substituted C6-10 aryl group, R4 represents a hydrogen or a cyano group, D represents -CONR6-, -CO- or -NR6CO-, R6 represents hydrogen or an optionally substituted C1-6 alkyl group, E represents -(CH2)m- whereupon m is an integer of 1 to 3, -CH2OCH2-, or -SCH2-, n is an integer of 0 to 3, and A represents an optionally substituted bicyclic heterocyclic group or bicyclic hydrocarbon group.
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Page/Page column 28
(2010/02/14)
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- Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor
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Starting from the tetrahydroisoquinoline SB-2770111, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19. which has high affinity for the dopamine D3 receptor (pKi 8.3) and ≥ 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%. t1/2 5.2h).
- Austin, Nigel E,Avenell, Kim Y,Boyfield, Izzy,Branch, Clive L,Hadley, Michael S,Jeffrey, Phillip,Johnson, Christopher N,Macdonald, Gregor J,Nash, David J,Riley, Graham J,Smith, Alexander B,Stemp, Geoffrey,Thewlis, Kevin M,Vong, Antonio K.K,Wood, Martyn D
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p. 685 - 688
(2007/10/03)
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