Bioavailable inhibitors

Compounds 674-676 are potent orally bioavailable inhibitors of tumor necrosis factor-a (TNF-a) production <2004BML4267, 2004JME2724>. 

Tetrahydropyrazolo[3,4-f]pyridines have been prepared as cannabinoid modulators <2007W0112399>. The pyra-zolo[3,4-4pyridine, Apixaban (BMS-562247), has been found to be a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor xa <2007JMC5339>. Several pyrazolo[3,4-f]pyridines have been found to be potent inhibitors of human eosinophil phosphodiesterase <2007JMC344>. 

Kaldor SW, Kalish VJ, Davies JF, Appelt K, Tatlock JH, Dressman BA, Campanale KM, Burgess JA, Lubbehusen PL, Muesing MA, Hatch SD, Shetty BV, Patick AK, Kosa MB, Khalil DA. AG1343 a potent orally bioavailable inhibitor of HIV-1 protease. J. Med. Chem. 1996 submitted for publication. 

The imidoyl chloride moiety of 5-chloro-l-alkyl-1,4-benzodiazepin-2-ones participates in Pd-catalyzed, Suzuki crosscoupling reactions, reacting with a range of functionalized aromatic boronic acids to provide an efficient and versatile approach to 5-aryl and 5-heteroaryl compounds (Scheme 19) <2003JOC2844>. This chemistry readily extends to 3-amino-substituted compounds that are orally bioavailable inhibitors of the aspartyl protease 7-secretase <2003BML4143>. 

A. K. Patick, S. H. Reich, K. S. Su, and J. H. Tatlock, Viracept (nelfinavir mesylate, AG1343) a potent, orally bioavailable inhibitor of HIV-1 protease,... 

H Tomoda, H Nishida, YK Kim, R Obata, T Sunazuka, S Omura, J Bordner, M Guadllana, PG Dormer, AB Smith III. Relative and absolute stereochemistry of pyripyropene A, a potent, bioavailable inhibitor of acyl-CoA cholesterol acyltransferase. J Am Chem Soc 116 12097-12098, 1994. 

Am. Cbem. Soc., 117,1181 (1995). Crystal Structure of HIV-1 Protease in Complex with VX-478, A Potent and Orally Bioavailable Inhibitor of the Enzyme. 

A number of steps were required to discover an orally bioavailable inhibitor in vivo similar to that seen with the N-hydroxyureas (2). The compound discovered was improved by structural modification of the naphthyl ring, and further introduction of a fluoro substituent to reduce susceptibility to metabolism. This compound was ZD2138 (12)(IC5o =... 

A novel class of orally bioavailable inhibitors by X-ray crystallographic screening... 

Figure 10.16 Three inhibitors of PDGF receptor tyrosine kinase, their oral bioavailabilities in rat as noted on days 1 and 4 of dosing, and whether or not they induced rat CYPs (He, W., et al. Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2 the synthesis and biological activities of RPR127963, an orally bioavailable inhibitor. Bioorg. Med. Chem. Lett. 2003, 75, 3097-3100.)...

L-167307 is an orally bioavailable inhibitor of p38 kinase. In vivo, it reduces secondary paw swelling in the rat adjuvant arthritis model with an ID50 of 7.4 mg/kg/day. Triarylpyrrole L-167307 was assembled using the Paal-Knorr pyrrole synthesis of a 1,4-diketone and ammonium acetate. ... 

Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator [81]... 

Frederickson, M., Callaghan, O., Chessari, G., Congreve, M., Cowan, S.R., Matthews, J.E., McMenamin, R., Smith, D.-M., Vinkovic, M., and Wallis, N.G. (2008) Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator. Journal of Medicinal Chemistry, 51,183-186. 

---