- Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism
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A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.
- Wehn, Paul M.,Harrington, Paul E.,Carlson, Timothy J.,Davis, James,Deprez, Pierre,Fotsch, Christopher H.,Grillo, Mark P.,Lu, Jenny Ying-Lin,Morony, Sean,Pattabiraman, Kanaka,Poon, Steve F.,Reagan, Jeff D.,St. Jean Jr., David J.,Temal, Taoues,Wang, Minghan,Yang, Yuhua,Henley III, Charles,Lively, Sarah E.
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p. 6625 - 6628
(2014/01/06)
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- DERIVATlVES OF UREA AND RELATED DIAMINES, METHODS FOR THEIR MANUFACTURE AND USES THEREFOR
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The present invention relates generally to compounds represented in Formula I, pharmaceutical compositions comprising them and methods of treating of diseases or disorders related to the function of the calcium sensing receptor. The invention also relates to processes for making such compounds and to intermediates useful in these processes
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Page/Page column 33
(2009/03/07)
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- Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides
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SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.
- Cumming, John G.,Cooper, Anne E.,Grime, Ken,Logan, Chris J.,McLaughlin, Sharon,Oldfield, John,Shaw, John S.,Tucker, Howard,Winter, Jon,Whittaker, David
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p. 5012 - 5015
(2007/10/03)
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- 1,4-Dihydropyridine derivatives
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A 1,4-dihydropyridine derivative having the formula (I): wherein, R1represents a substituted or unsubstituted phenyl or pyridyl group, R2represents a C1to C5lower alkyl group, R3represents a substituted or unsubstituted C1to C8alkyl, alkenyl, alkynyl or substituted or unsubstituted C3to C7cycloalkyl or cycloalkenyl group, R4represents —A—R5, wherein A represents a C3to C5alkynylene group having one triple bond, and R5represents a substituted or unsubstituted pyridyl, quinolyl, isoquinolyl or pyrimidyl group and a drug for overcoming resistance to an anti-cancer drug or a drug increasing the effect of an anti-cancer drug containing as an effective ingredient the derivative or its pharmacologically acceptable salt or hydrate.
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