Subtype selective inhibitors

Another chemotype displaying appreciable isoform selectivity is the 5-benzoyloxy-3,4-dihydroisoquinolin-l(2H)-one (37), displaying ICso = 0.8 and 13 pM against PARP-2 and PARP-1, respectively [36]. Interestingly, 38 is a selective PARP-1 inhibitor, pICso = 7.35, displaying around 100-fold selectivity for PARP-1 over PARP-2 [34], 

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Thomsen, C., Sprensen, P. 0., and Egebjerg, J. (1997) l-(3-(9H-carbazol-9-yl)-l- propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter. Br. J. Pharmacol. 120,983-985. 

Kranz M, Wall M, Evans B et al (2009) Identification of PDE4B over 4D subtype-selective inhibitors revealing an unprecedented binding mode. Bioorg Med Chem 17 5336-5341... 

Fig. 8. Allosteric sites in the mGluR 7TM. The chemical structures of the allosteric inhibitors MPEP, EM-TBPC, BAY36-7620, and CPCCOEt, and the allosteric potentiator Ro 67-7476 are given. The crucial residues or regions for the subtype selectivity of each of the compounds are stated and shown in a schematic illustration of the mGluRl 7TM viewed from the extracellular side of the cell membrane. The residues in mGluRl corresponding to those involved in MPEP binding to mGluR5 are also shown in the illustration.

Maly, D.J., Choong, I.C., Ellman, J.A. Combinatorial target-guided ligand assembly identification of potent subtype-selective c-Src inhibitors. 

It is evident that the quest for selective HDAC inhibitors has just be-gim and that the optimal HDAC subtype selectivity profile for an anticancer drug based on HDAC inhibition is still far from being established. Never-... 

Tiotropium is a QTA representing a synthetic ester of N-methylated scopine (Fig. 1). This drug is clinically used as anticholinergic long-acting bronchodilator applied once daily as aerosolized solution to treat airway diseases such as COPD. Tiotropium is considered as a selective inhibitor of MR subtype Ml and M3 thus not enhancing mucus production [31]. 

Tetrahydrochromones have also found applications as inhibitors of excitatory amino acid transporter Subtype 1(EAAT1) [64]. For example, compound 145 (Fig. 19) was the first reported submicromolar inhibitor of EAATl with >400-fold selectivity over EAAT2 and EAAT3. The subtype selectivity of 145 made that compound a highly valuable tool to further explore the physiological role of EAATl. 

Sildenafil is a selective inhibitor of phosphodiesterase type-5 that is orally effective in the treatment of erectile dysfunction. Its pharmacological actions are a consequence of prolonging the signaling actions of NO because this drug prevents cGMP hydrolysis by inhibition of a cGMP phosphodiesterase V subtype enriched in penile smooth muscle (1, 10, 143). 

Sagot E, Jensen AA, Pickering DS et al (2008) Chemo-enzymatic synthesis of (2S, 4R)-2-amino-4-(3-(2, 2-diphenylethylamino)-3-oxopropyl)pentanedioic acid a novel selective inhibitor of human excitatory amino acid transporter subtype 2. J Med Chem 51 4085-4092... 

Jensen AA, Erichsen MN, Nielsen CW et al (2009) Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1. J Med Chem 52 912-915... 

PDE IV inhibitors, as well as some combined PDE IIl/IV inhibitors, are currently under development for the treatment of asthma (Christensen and Torphy, 1994 Nicholson and Shahid, 1994). The basis for this development includes bronchodilatory activity directly related to inhibition of PDE IV, and/or PDE III, in airway smooth muscle, as well as the antiinflammatory activity of these compounds. PDE IV is the major cAMP PDE isozyme present in inflammatory cell types and inhibition of PDE IV has been linked to elevation of cAMP and inhibition of histamine or leukotriene release from mast cells, inhibition of oxygen free radical release from eosinophils or neutrophils, inhibition of adhesion, migration, or activation of eosinophils, and inhibition of TNF-a release from human monocytes (see Nicholson and Shahid, 1994, or Christensen and Torphy, 1994, for some reviews). There are now known to be at least four sub-types of PDE IV that are encoded by different cDNAs (Bolger et al., 1993 Davis et al, 1989 Livi et al., 1990). Although sequence homology of 75-90% is evident among subtypes, key differences, as well as cellular distribution, are apparent. Currently there are no selective inhibitors of the PDE IV subtypes. 

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