Design and Synthesis of Novel 1,3-Dioxane-2-carboxylic Acid Derivatives as PPARα/γ Dual Agonists

被引：1

作者：

Pingali, Harikishore ^{[1
,2
]}

Jain, Mukul ^{[2
]}

Shah, Shailesh ^{[1
]}

Makadia, Pankaj ^{[2
]}

Zaware, Pandurang ^{[2
]}

Jamili, Jeevankumar ^{[2
]}

Sairam, Kalapatapu V. V. M. ^{[2
]}

Patil, Pravin ^{[2
]}

Suthar, Dinesh ^{[2
]}

Giri, Suresh ^{[2
]}

Patel, Harilal ^{[2
]}

Patel, Pankaj ^{[2
]}

机构：

[1] Maharaja Sayajirao Univ Baroda, Dept Chem, Fac Sci, Vadodara 390001, India

[2] Zydus Res Ctr, Ahmadabad 382210, Gujarat, India

来源：

LETTERS IN DRUG DESIGN & DISCOVERY | 2010年 / 7卷 / 06期

关键词：

PPAR agonist; PPAR alpha/gamma dual agonists; Type; 2; diabetes; 1,3-dioxane carboxylic acid; ACTIVATED RECEPTOR-ALPHA; HYPOLIPIDEMIC AGENTS; INSULIN SENSITIVITY; GAMMA AGONISTS; FATTY-ACIDS; THIAZOLIDINEDIONE; INFLAMMATION; METABOLISM; FENOFIBRATE; SELECTIVITY;

D O I：

10.2174/157018010791306533

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

1,3-dioxane carboxylic acid derivatives were prepared based on our previous studies directed towards identifying novel pharmacophore for the development of PPAR alpha/gamma dual agonists. Based on the typical topology of PPAR agonists we focused our design approach on modifying lipophilic tail and prepared a series of compounds by replacing the oxazole moiety of our previously reported compound with optimized lipophilic groups. Compound 8a was found to be a weak PPAR activator but exhibited potent hypolipidemic and anti-hyperglycemic activities in vivo due to superior bioavailability, whereas 8f exhibited potent in vitro and invivo effects. The activity of 8f is further supported by molecular docking study.

引用

页码：421 / 429

页数：9

共 47 条

[1] The mechanisms of action of PPARs [J].

Berger, J ;

Moller, DE .

ANNUAL REVIEW OF MEDICINE, 2002, 53 :409-435

[2] Enantioselective synthesis of 2,3-disubstituted piperidines from (S)-methylpyroglutamate [J].

Calvez, O ;

Chiaroni, A ;

Langlois, N .

TETRAHEDRON LETTERS, 1998, 39 (51) :9447-9450

[3] [[OMEGA-(HETEROCYCLYLAMINO)ALKOXY]BENZYL]-2,4-THIAZOLIDINEDIONES AS POTENT ANTIHYPERGLYCEMIC AGENTS [J].

CANTELLO, BCC ;

CAWTHORNE, MA ;

COTTAM, GP ;

DUFF, PT ;

HAIGH, D ;

KINDLEY, RM ;

LISTER, CA ;

SMITH, SA ;

THURLBY, PL .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (23) :3977-3985

[4] Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight [J].

Chaput, E ;

Saladin, R ;

Silvestre, M ;

Edgar, AD .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 271 (02) :445-450

[5] Nuclear receptors and lipid physiology: Opening the X-files [J].

Chawla, A ;

Repa, JJ ;

Evans, RM ;

Mangelsdorf, DJ .

SCIENCE, 2001, 294 (5548) :1866-1870

[6] Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1 [J].

Delerive, P ;

De Bosscher, K ;

Besnard, S ;

Vanden Berghe, W ;

Peters, JM ;

Gonzalez, FJ ;

Fruchart, JC ;

Tedgui, A ;

Haegeman, G ;

Staels, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (45) :32048-32054

[7] Peroxisome proliferator-activated receptors in inflammation control [J].

Delerive, P ;

Fruchart, JC ;

Staels, B .

JOURNAL OF ENDOCRINOLOGY, 2001, 169 (03) :453-459

[8] Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [muraglitazar BMS-298585], a novel peroxisome proliferator-activated receptor α/γ dual agonist with efficacious glucose and lipid-lowering activities [J].

Devasthale, PV ;

Chen, S ;

Jeon, Y ;

Qu, FC ;

Shao, CN ;

Wang, W ;

Zhang, H ;

Cap, M ;

Farrelly, D ;

Golla, R ;

Grover, G ;

Harrity, T ;

Ma, ZP ;

Moore, L ;

Ren, J ;

Seethala, R ;

Cheng, L ;

Sleph, P ;

Sun, W ;

Tieman, A ;

Wetterau, JR ;

Doweyko, A ;

Chandrasena, G ;

Chang, SY ;

Humphreys, WG ;

Sasseville, VG ;

Biller, SA ;

Ryono, DE ;

Selan, F ;

Hariharan, N ;

Cheng, PTW .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (06) :2248-2250

[9]

Ergas D, 2002, ISR MED ASSOC J, V4, P34

[10] PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome [J].

Fievet, Catherine ;

Fruchart, Jean-Charles ;

Staels, Bart .

CURRENT OPINION IN PHARMACOLOGY, 2006, 6 (06) :606-614

← 1 2 3 4 5 →