Orally active inhibitors

Aicher, T.D., Anderson, R.C., Bebernitz, G.R.,ei al. (1999) (/ )-3,3,3-Trifluoro-2-hydroxy-2-methylpropiona-mides are orally active inhibitors of pyruvate dehydrogenase kinase. Journal of Medicinal Chemistry, 42, 2741-2746. 

Chen P, Doweyko AM, Norris D, et al. Imidazo-quinoxahne Src-family kinase p56 inhibitors SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-l-piper-azinyl) imidazo [l,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity J Med Chem 2004 47, 4517-29. 

Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Curwen JO, Hennequin LF, et al. ZD4190 an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy. Cancer Res 2000 60 970-975. 

The ketene dithioacetal method group has proved useful for the synthesis of a number of biologically interesting molecules <2000BML703, 2004EJM969>, including 5-cyanopyrimidine derivatives which are orally active inhibitors... 

Rofecoxib, (MK 0966, Vioxx 4-(4-Methylsulfonylphenyl)-3-Phenyl-2(5H)-Furanone), a Selective and Orally Active Inhibitor of Cycooxygenase-2, Synthesis 2001,1778-1779. 

Substituted derivatives of 3-amino-5-phenyl-l,4-benzodiazepin-2-one continue to be a rich source of compounds that display a diverse range of biological properties. The 2-fluorophenylurea 166 is an inhibitor of respiratory syncytial virus (RSV) that appears to act by inhibiting the nucleocapsid (N) protein <2006JME2311, 2007JME1685>. This compound is the first orally active inhibitor of RSV to be advanced into clinical studies. 

DS Karanewsky, MC Badia, DW Cushman, JM DeForrest, T Dejneka, MJ Loots, MG Perri, EW Petrillo, JR Powell. (Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-l-[6-amino-2-[[hy-droxy(4-phenylbutyl)phosphinyl]oxy]-l-oxohexyl]-L-proline, a novel orally active inhibitor of ACE. J Med Chem 31 204-212, 1988. 

Ziircher G, Keller HH, Kettler R, Borgulya J, Bonetti EP, Eigenmann R, Da Prada M. Ro 40-7592, a novel, very potent, and orally active inhibitor of catechol-O-methyltransferase a pharmacological study in rats. Adv. Neurol, 1990, 53, 497-503. 

Herbert JM, Bernat A, Dol F et al. (1996) DX 9065A, a novel, synthetic selective and orally active inhibitor of factor Xa in vitro and in vivo studies. J Pharmacol Exp Therapeutics 276 1030-1038... 

Taniuchi Y, Sakai Y, Hisamichi N et al. (1998) Biochemical and pharmacological characterization of YM-60828, a newly synthesized and orally active inhibitor of human Factor Xa. Thromb Haemost 79 543-548... 

Many pharmaceutical companies are actively working on the development of orally active inhibitors of the serine protease thrombin as one important enzyme in the blood coagulation cascade. In many cases, however, the systemic exposure to thrombin inhibitors... 

Birkett DJ, Mackenzie PI, Veronese ME, Miners JO (1993) In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci 14 292-294 Bloomer JC, Boyd HF, Hickey DMB et al. (2001) 1-(Arylpiperazinylamidoalkyl)-pyrimidones Orally Active Inhibitors of Lipoprotein-Associated Phospholipase A2. Bioorg Med Chem Lett 11 1925-1929 Brandon EFA, Raap CD, Meijerman I et al. (2003) An update on in vitro test methods in human hepatic drug biotransformation research pros and cons. Toxicol Applied Pharmacol 189 233-246... 

Sidelmann UG, Cornett C, Tjornelund J, Hansen SH (1996) A comparative study of precision cut liver slices, hepatocytes and liver microsomes from the Wistar rat using metronidazole as a model substance. Xenobiotica 26 709-722 Stratford RE, Clay MP, Heinz BA et al. (1999) Application of Oral Bioavailability Surrogates in the Design of Orally Active Inhibitors of Rhinovirus Replication. J Pharm Sci 88 747-753... 

Scientists at Boehringer Ingelheim recently described (195,196) their discovery of an orally active inhibitor of MAPK p38a, compound (85)(BIRB-796), that is very different... 

Figure 13. Design of orally active inhibitors of elastase at Zeneca. The initial idea, to replace the Ala-Pro unit by a pyridone, led to 10. Later, pyrimidones were investigated. In this structural class, very potent elastase inhibitors were found, e.g., 12. Very good in vivo properties are observed for 13. The p-flu-orophenyl- or p-aminophenyl substituent improves the lipophilic contact with the enzyme.

J., Liras, J. L., Vaughn, M. Discovery of 3-OH-3-methylpipecolic hydroxamates potent orally active inhibitors of aggrecanase and MMP-13. Bioorg. Med. Chem. Lett. 2005, 75(14), 3385-3388. 

Pavia, M. R., Lobbestael, S. J., Nugiel, D., Mayhugh, D. R., Gregor, V. E., Taylor, C. P., Schwarz, R. D., Brahce, L., Vartanian, M. G. Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake. J. Med. Chem. 1992, 55, 4238-4248. 

Rahuel, J., Rasetti, V., Maibaum, J., Riieger, H., Goschke, R., Cohen, N.-C., Stutz, S., Cumin, E, Euhrer, W., Wood, J. M., Griitter, M. G. Structure-based drug design the discovery of novel nonpeptide orally active inhibitors of human rennin. Chem. Biol. 2000, 7, 493—504. 

The ready formation of esters of P amino acids by reduction of the correspond ing imines/enamines (Table 4.6, entries 12 14), which in turn can be prepared from the readily available P keto esters, allowed an expedient synthesis of SCH48461 (56), a potent, orally active inhibitor of cholesterol absorption [22]. Enamine 36n (Scheme 4.6) was reduced (via imine lOn) with ChSiH in the presence of Sigamide (35) to afford the P amino ester ISn (80% isolated yield, 88% ee), whose treatment with methylmagnesium bromide (acting as a base) produced p lactam 55 (92%). Enolization of the latter derivative with LDA followed by alkylation with cinnamyl bromide and catalytic hydrogenation afforded 56 in 77% overall yield for the last two steps (S. Stoncius, A.V. Malkov, and P. Kocovsky, unpublished results). 

Scheme 4.21 Blocking of unproductive metabolic pathways by fluorination as a design tool for an orally active inhibitor of cholesterol absorption [53a]. The result of this rational approach (SCH 58235) is 50 times more active than the conceptual starting compound SCH 48461. (ED50 refers to reduction of liver cholesterol esters in hamsters).

Potts GO, Creange JE, Hardomg HR, et al. Trilostane, an orally active inhibitor of steroid biosynthesis. Steroids 1978 32 257-267. 

Captopril, l-[(2S)-3-mercapto-2-methyl-propionyl]-L-proline, the first orally active inhibitor of the angiotensin-converting enzyme (ACE) on the market. The positive effects of captopril and other ACE inhibitors like enalapril in hypertension and heart failure result primarily from suppression of the renin-angiotensin-aldosterone system. Captopril causes a fall in blood pressure in hypertensive patients [M. A. Ondetti et al.. Science 1977,196,441 ... 

Enalapril, (S)-l-[N-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline, an orally active inhibitor of the angiotensinconverting enzyme (ACE). After oral administration, the prodrug enalapril (ICso = 1.2 X 10 M) is primarily bioactivated in the liver by hydrolysis of the ethyl ester to yield enalaprilat (IC50 =... 

See Rahuel, J. et al. Structure-based drug design The discovery of novel nonpeptide orally active inhibitors of human renin. Chem. Biol. 2000, 7, 493-504. 

---