A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.

This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.

Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.

A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The preparation of a variety of derivatives of 2-oxa-1,3,4,10-tetraazacyclopenta[b] fluoren-9-one 1 is described. A series of substituted indan-1-ones were prepared and oxidized with N-bromosuccinimide and dimethyl sulfoxide to the corresponding ninhydrin derivatives. Cyclization of the ninhydrins with furazan-3,4-diamine yielded the target tetracycles. Appropiate choice of substituents in ninhydrins led to a preference for one regioisomer in the target tetracycles. This permitted the synthesis of a variety of 8-substituted heterocycles. In those instances where isomer formation was possible, structural assignments were confirmed by X-ray crystallography.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A six-step synthetic route to four lipophilic crown ethers with intraannular carboxylic acid groups and ring sizes of 15-crown-4, 18-crown-5, 21-crown-6 and 24-crown-7 is described. Eight new polyether compounds that bear inward-facing bromo and formate ester substituents are prepared as synthetic intermediates. Selectivities and efficiencies of the four new lipophilic crown ether carboxylic acids in competitive alkali metal cation extraction from aqueous solutions into chloroform are evaluated.

The preparation of several novel 3,5-substituted-indole-2-carboxamides is described. A 5-nitro-indole-2-carboxylate was elaborated to the 3-benzhydryl ester, N-substituted ester, and carboxylic acid intermediates, followed by conversion to the amide and then reduction of the 5-nitro group to the amine, Indole-2-carboxamides with 3-benzyl and 3-phenyl substituents were prepared in four steps fi om either a 3-bromo indole ester using the Suzuki reaction or from a 3-keto substituted indole ester. N-Alkylation of ethyl indole-2-carboxylate, followed by amidation and catalytic addition of 9-hydroxyxanthene gave a 3-xanthyl-indole-2-carboxamide analog and a spiropyrrolo indole as a side product.

The addition of organometallic reagents to the 13b-position of the indolo[2',3':3,4]pyrido[1,2-b]isoquinoline imminium salt 4 is described. Reaction of 4 with tetraallyl tin in 2-methoxyethanol gave the allyl adduct 7 in moderate yield. Further elaboration of 7 yielded the pentacyclic benzylidene alcohols 13 and 14. Structure elucidation of the compounds prepared was achieved by a combination of H-1 nmr spectroscopy and X-ray crystallography.