This manuscript describes the design and synthesis of a series of N-iso-propyl pyrrole-based inhibitors of HMG-CoA reductase for 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.
Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet−Spengler condensation (Scheme ). Efficient methods for the synthesis of each ...compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.
The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine–piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 ...binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
In the context of our ghrelin inverse agonist program, a functionalized bromoindane 3 provided a versatile intermediate for structure–activity relationship studies. After developing operationally ...simple cross-coupling reactions, a broad spectrum of chemical space was successfully explored. Optimization of a one-pot borylation/Suzuki sequence provided the desired products in high yield with low loading of the palladium catalyst. High yields of N-linked heterocyclic analogues were obtained through palladium catalyzed C–N bond formation. In addition, carboxylation of the bromoindane provided an indane carboxylic acid for further diversification.
The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the ...clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (
3R,
5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1
H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (
26) as a candidate for treating hypercholesterlemia. Clinical evaluation of
26 (PF-03491165), as well as the previously reported
2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.
The synthesis and structure–activity relationships of a series of novel and selective benzothiophene, benzofuran and indole-based peroxisome proliferator-activated receptor δ agonists.
Recent ...literature has suggested the benefit of selective PPARδ 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 PPARδ 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 PPARδ versus the PPARα and PPARγ subtypes.
A series of ketopiperazine-based renin inhibitors designed to interact in the S
3 sub-pocket of the renin protein were evaluated for renin inhibitory activity. The investigation revealed that linear ...and sterically small side chain substituents are preferred in the S
3 sub-pocket for optimal renin inhibition. Polar groups in the S
3 sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with c
log
P’s
⩽
3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
A systematic investigation of the S
3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S
3 sub-pocket for optimal renin inhibition. Polar groups in the S
3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with c
log
P’s
⩽
3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
The synthesis of 6-methoxylavendamycin methyl ester (39) and 6-methoxy detnethyllavendamycin methyl ester (40) is reported. Also the synthesis of 7-propionamido-2-methylquinoline-5,8-dione (33) and ...7propionamido-3-methylquinoline-5,8-dione (34) via the Diels-Alder reaction is described.The Pictet-Spengler condensation of 7-amino-6-methoxy-2-formylquinoline-5,8-dione (37) with 8-methyltryptophan methyl ester (4) and tryptophan methyl ester (38), produced respectively the lavendamycin analogs 39 and 40.Aldehyde 37 was prepared by the oxidation of 7-amino-6-methoxy-2methylauinoline-5,8-dione (47) with selenium dioxide under reflux in dry 1,4-dioxane.Our original plan for the synthesis of aldehyde 37 via 7-bromo-6methoxy-2-methylquinoline-5,8-dione (36) was not successful. The DielsAlder reaction of 3-methoxy-2,6-dibromobenzoquinone (35) and N-(O-(t-butyldimethylsilyloxy)-2-methyl-1-aza-1,3-butadiene (11) gave a very low yield of 36 and consequently this route was abandoned.An alternate known multistep route was chosen to produce the bromoquinolinedione 36. Reaction of 4-methoxy-2-nitroaniline (41) with crotonaldehyde (42) gave 6-methoxy-2-methyl-8-nitroquinoline-5,8-dione (43). Subsequent nitration, reduction, oxidation, and bromination of mononitroquinoline 43 yielded the desired bromoquinolinedione 36 with success. A change to Boger's procedure in the next reaction involving the azido intermediate 46 was done due to its effectiveness in producing a greater yield and purer product than that of Liao's procedure. The final preparation of 7-amino-6-methoxy-2-methylquinoline-5,8-dione (47) was accomplished by the hydrogenation of azidoquinolinedione 46 in the presence of platinum oxide in anhydrous methanol.Two other quinolinediones, 33 and 34, were earlier synthesized using the Diels-Alder reaction. Quinolinediones 33 and 34 were prepared by reacting 2-propionamido-6-bromobenzoquinone (32) with azadienes 11 and 19 to respectively yield 7-propionamido-2-methylquinoline-5,8-dione (33) and 7propionamido-3-methylquinoline-5,8-dione (34).Bromobenzoquinone 32 was prepared according to Kelly's method of preparation. 2,4-Dibromophenol (48) was nitrated, reduced, propionylated, hydrolyzed, and finally oxidized to produce 2-propionamido-6bromobenzoquinone (32).
Department of Chemistry
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