- Synthesis and Evaluation of PPARδAgonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis
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We synthesized a directed library of compounds to explore the structure-activity relationships of peroxisome proliferator-activated receptor δ(PPARδ) activation relative to mesenchymal stem cell (MSC) osteogenesis. Our scaffold used para-substituted cinnamic acids as a polar headgroup, a heteroatom and heterocycle core connecting units, and substituted phenyl groups for the lipophilic tail. Compounds were screened for their ability to increase osteogenesis in MSCs, and the most promising were examined for subunit specificity using a quantitative PPAR transactivation assay. Six compounds were selected for in vivo studies in an ovariectomized mouse model of human postmenopausal osteoporosis. Four compounds improved bone density in vivo, with two (12d and 31a) having activity comparable to that of GW0742, a well-studied PPARδ-selective agonist. 31a (2-methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamic acid) had the highest selectivity for PPARδcompared to other subtypes, its selectivity far exceeding that of GW0742. Our results confirm that PPARδis a new drug target for possible treatment of osteoporosis via in situ manipulation of MSCs.
- Kress, Brian J.,Kim, Dong Hyun,Mayo, Jared R.,Farris, Jeffery T.,Heck, Benjamin,Sarver, Jeffrey G.,Andy, Divya,Trendel, Jill A.,Heck, Bruce E.,Erhardt, Paul W.
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p. 6996 - 7032
(2021/05/29)
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- Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
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The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.
- Li, Zheng,Chen, Yueming,Zhou, Zongtao,Deng, Liming,Xu, Yawen,Hu, Lijun,Liu, Bing,Zhang, Luyong
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p. 352 - 365
(2019/01/04)
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- Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
- Li, Zheng,Qiu, Qianqian,Xu, Xue,Wang, Xuekun,Jiao, Lei,Su, Xin,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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p. 246 - 257
(2016/03/08)
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- ANALOGS OF PPARO AND 20-OH-PGE2, AND METHODS OF USING THE SAME
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Analogs of PPAR5 and analogs of 20-OH-PGE2, which are PPAR5 agonists and 20-OH-PGE2 antagonists, respectively, and methods of using the same for inducing osteogenesis or chondrogenesis, are disclosed.
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Paragraph 00133; 00134; 00145; 00146
(2014/10/04)
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- 4-OXY-N-[1 ,3,4]-THIADIAZOL-2-YL-BENZENE SULFONAMIDES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS PHARMACEUTICALS
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The invention relates to 4-oxy-N-[1 ,3,4]-thiadiazol-2-yl-benzene sulfonamides and to their physiologically acceptable salts and physiologically functional derivatives showing PPARalpha, PPARdelta and PPARgamma agonist activity. What is described are comp
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Page/Page column 67-68
(2008/06/13)
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- PROCESS FOR PREPARING LIGANDS OF PPARDELTA AND THE INTERMEDIATE COMPOUNDS FOR PREPARING THE SAME
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The present invention provides a process for preparing thiazole derivatives of formula (I), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPAR δ ), and also provides compounds of formula (II), (IV), (X), (XI) and (XII), intermediate compounds for preparation of the above compounds of formula (I).
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- Synthesis of the PPARβ/δ-selective agonist GW501516 and C4-thiazole-substituted analogs
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Sequential, position-selective, Pd-catalyzed cross-coupling reactions of 2,4-dibromo-5-hydroxymethylthiazole provided the scaffold for the synthesis of GW501516, the most potent PPARβ/δ agonist yet described, and equally selective analogs at the thiazole-
- Pereira, Raquel,Gaudon, Claudine,Iglesias, Beatriz,Germain, Pierre,Gronemeyer, Hinrich,De Lera, Angel R.
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- Oxadiazolones, processes for their preparation and their use as pharmaceuticals
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The invention relates to oxadiazolones and to their physiologically acceptable salts and physiologically functional derivatives showing PPARdelta agonist activity. What is described are compounds of the formula I, in which the radicals are as defined, and
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- (5- (2-PHENYL)-THIAZOL-5-YLMETHOXY)-INDOL-1-YL) -ACETIC ACID DERIVATIVES AND RELATED COMPOUNDS AS MODULATORS OF THE HUMAN PPAR-DELTA RECEPTOR FOR THE TREATMENT OF METABOLIC DISORDERS SUCH AS TYPE 2 DIABETES
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Disclosed are compounds having the structure of Formula (I) and pharmaceutically acceptable salts and solvates thereof [A]-[B]-[C] (I) wherein (a) [A] is [H]-[L]; wherein [H] represents a CCOH (or a hydrolyzable ester thereof) or tetrazole group [L] is: formula (II), b) [B] is a ring system selected from the group consisting of: e.g. formula (III); (IIIA), c) [C] is e.g. formula (IV); the other substituents and variables are defined in the claims; as modulators of the human PPAR-delta receptor for the treatment of metabolic disorders such as type 2 diabetes.
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Page/Page column 116
(2008/06/13)
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- HETEROCYCLIC COMPOUNDS AS MODULATORS OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS, USEFUL FOR THE TREATMENT AND/OR PREVENTION OF DISORDERS MODULATED BY A PPAR
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The present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, which is useful in treating or preventing disorders mediated by a peroxisome proliferator activated receptor (PPAR) such as syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to syndrome X and cardiovascular diseases.
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Page/Page column 90; 160
(2010/02/11)
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- Compounds that modulate PPAR activity and methods of preparation
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This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing hyperlipidemia and hypercholesteremia in a mammal. The present invention also discloses methods for making the disclosed compounds.
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- CHEMICAL COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolysable ester thereof, wherein: (...).
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- Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ) - Synthesis and biological activity
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We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
- Sznaidman, Marcos L.,Haffner, Curt D.,Maloney, Patrick R.,Fivush, Adam,Chao, Esther,Goreham, Donna,Sierra, Michael L.,LeGrumelec, Christelle,Xu, H. Eric,Montana, Valerie G.,Lambert, Millard H.,Willson, Timothy M.,Oliver Jr., William R.,Sternbach, Daniel D.
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p. 1517 - 1521
(2007/10/03)
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- PROCESS FOR PREPARING THIAZOLE DERIVATIVE AND THE INTERMEDIATE COMPOUNDS FOR PREPARING THE SAME
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The present invention provides a process for preparing thiazole derivatives of formula (XI), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPARδ), and also provides processes for compounds of formula (VI), (VII)
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