- Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model
-
Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity, and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of coadministered pharmaceuticals that are metabolized by CYP3A4. On the basis of our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety, and aromaticity of the side group analogous to Phe-2 of ritonavir and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable submicromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.
- Kaur, Parminder,Chamberlin, A. Richard,Poulos, Thomas L.,Sevrioukova, Irina F.
-
-
Read Online
- NOVEL CYP34A-SPECIFIC INHIBITORS AND METHODS OF USING SAME
-
The present invention includes novel compositions inhibiting CYP3 A4. The present invention further includes a novel method of inhibiting CYP3A4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is further administered at least one additional therapeutic agent.
- -
-
Page/Page column 41
(2017/03/28)
-
- ISOINDOLINONE AND PYRROLOPYRIDINONE DERIVATIVES AS AKT INHIBITORS
-
The present invention provides isoindolinone and pyrrolopyridinone derivatives, as well as their compositions and methods of use, that inhibit the activity of the serine/threonine kinase, Akt, and are useful in the treatment of diseases related to the act
- -
-
Paragraph 0468; 0469
(2013/04/24)
-
- RENIN INHIBITORS AND METHOD OF USE THEREOF
-
Disclosed are aspartic protease inhibitors represented by the following Formula: wherein R1 , R2, R3, R4, R5, R6, R7a, R7b and n are as defined herein, or a pharmaceut
- -
-
Page/Page column 54
(2010/01/12)
-
- Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors
-
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitor
- Seefeld, Mark A.,Rouse, Meagan B.,McNulty, Kenneth C.,Sun, Lihui,Wang, Jizhou,Yamashita, Dennis S.,Luengo, Juan I.,Zhang, ShuYun,Minthorn, Elisabeth A.,Concha, Nestor O.,Heerding, Dirk A.
-
scheme or table
p. 2244 - 2248
(2009/12/07)
-
- RENIN INHIBITORS
-
Described are compounds that bind to aspartic proteases to inhibit their activity. They are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also described are methods of use of the compounds described herein in ameliorating or treating aspartic protease related disorders in a subject in need thereof.
- -
-
Page/Page column 108
(2009/01/23)
-
- Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase
-
Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper.
- Thomas, Sheela A.,Li, Tongmei,Woods, Keith W.,Song, Xiaohong,Packard, Garrick,Fischer, John P.,Diebold, Robert B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Johnson, Eric F.,Bouska, Jennifer J.,Olson, Amanda,Guan, Ran,Magnone, Shayna R.,Marsh, Kennan,Luo, Yan,Rosenberg, Saul H.,Giranda, Vincent L.,Li, Qun
-
p. 3740 - 3744
(2007/10/03)
-
- Exploration of the P1 SAR of aldehyde cathepsin K inhibitors.
-
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
- Catalano, John G,Deaton, David N,Furfine, Eric S,Hassell, Annie M,McFadyen, Robert B,Miller, Aaron B,Miller, Larry R,Shewchuk, Lisa M,Willard Jr., Derril H,Wright, Lois L
-
p. 275 - 278
(2007/10/03)
-
- Reductions of aromatic amino acids and derivatives
-
Catalytic reduction of phenylalanine and phenylglycine derivatives can be achieved with rhodium on carbon or alumina to give good yields of the corresponding cyclohexyl derivatives. The procedure can be scaled.
- Ager, David J.,Prakash, Indra
-
p. 164 - 167
(2013/09/05)
-
- Asymmetric synthesis of β-amino alcohols and 1,2-diamines through DuPHOS-Rh catalysed hydrogenation
-
A novel enantioselective synthesis of β-amino alcohols and 1,2-diamines is reported which incorporates the first description of the asymmetric hydrogenation of dehydro-β-amino alcohols and dehydro-α-amino aldoximes.
- Burk, Mark J.,Johnson, Nicholas B.,Lee, Jeffrey R.
-
p. 6685 - 6688
(2007/10/03)
-
- Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity
-
Synthesis of a library of secondary benzylic amines based on the Sebti- Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC50 of 8 nM) which lacked the p
- Henry Jr., Kenneth J.,Wasicak, James,Tasker, Andrew S.,Cohen, Jerome,Ewing, Patricia,Mitten, Michael,Larsen, John J.,Kalvin, Douglas M.,Swenson, Rolf,Ng, Shi-Chung,Saeed, Badr,Cherian, Sajeev,Sham, Hing,Rosenberg, Saul H.
-
p. 4844 - 4852
(2007/10/03)
-
- Potent and Selective Inhibitors of an Aspartyl Protease-like Endothelin Converting Enzyme Identified in Rat Lung
-
Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed.Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series.Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity.Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity.Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D.Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing.Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.
- Shiosaki, Kazumi,Tasker, Andrew S.,Sullivan, Gerard M.,Sorensen, Bryan K.,Geldern, Thomas W. von,et al.
-
p. 468 - 478
(2007/10/02)
-
- Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation
-
Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, β-amino thiols were found to be the most
- Fournie-Zaluski,Coric,Turcaud,Bruetschy,Lucas,Noble,Roques
-
p. 1259 - 1266
(2007/10/02)
-
- Novel amino acid derivatives possessing renin-inhibitory activities
-
An amino acid derivative of the general formula: wherein, R1? is a lower alkyl group and R11 is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R1? and R11 are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+ 1-O-CO-(n is as defined above) or R13 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H?C)n-O-, R12-NH-(n and R12 are as defined above) and pyridyl group; X is-CH?-,-O-or-NH-and Y is-O-or-NH-; wherein (wherein Z is-O-,-S-,-S(O)-,-S(O)?-,-CH?-,-CH(OH)-,---,-NH-or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R? is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.
- -
-
-
- A Synthesis of Protected Aminoalkyl Epoxides from α-Amino Acids
-
The synthesis of alkylamino epoxides C is presented.Key steps include the synthesis of amino aldehyde 5 by reduction (DIBAH) of ester 3 or by oxidation of N-protected amino alcohol 4, both edducts of which are derived from amino acids.A study of the olefination of aldehyde 5 with unstabilized ylides is presented, and protected allylic amino 6, obtained in good to excellent optical purity, is oxidized (MCPBA) to epoxide C.Threo selectivity is observed in the epoxidation reaction.
- Luly, Jay R.,Dellaria, Joseph F.,Plattner, Jacob J.,Soderquist, Jeffrey L.,Yi, Nwe
-
p. 1487 - 1492
(2007/10/02)
-