title: N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.
abstract: 3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.
authors.affiliation: Glaxo Wellcome Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. jec1296@glaxowellcome.com
authors.forename: J E
authors.initials: JE
authors.lastname: Cobb
authors.forename: S G
authors.initials: SG
authors.lastname: Blanchard
authors.forename: E G
authors.initials: EG
authors.lastname: Boswell
authors.forename: K K
authors.initials: KK
authors.lastname: Brown
authors.forename: P S
authors.initials: PS
authors.lastname: Charifson
authors.forename: J P
authors.initials: JP
authors.lastname: Cooper
authors.forename: J L
authors.initials: JL
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Dezube
authors.forename: B R
authors.initials: BR
authors.lastname: Henke
authors.forename: E A
authors.initials: EA
authors.lastname: Hull-Ryde
authors.forename: D H
authors.initials: DH
authors.lastname: Lake
authors.forename: J M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: W
authors.initials: W
authors.lastname: Oliver
authors.forename: J
authors.initials: J
authors.lastname: Oplinger
authors.forename: M
authors.initials: M
authors.lastname: Pentti
authors.forename: D J
authors.initials: DJ
authors.lastname: Parks
authors.forename: K D
authors.initials: KD
authors.lastname: Plunket
authors.forename: W Q
authors.initials: WQ
authors.lastname: Tong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists*; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062367:ortho-Aminobenzoates
chemical_list: D001565:Benzoates; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D008055:Lipids; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C116285:methyl 2-(1-carboxy-2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)ethylamino)benzoate; D062367:ortho-Aminobenzoates; D014443:Tyrosine