Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

BMS-823778 (), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED = 0.

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 0.

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors.

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.

Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors.

The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.

Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.

Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species.

Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.

We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.

Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.

The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.

Synthesis and evaluation of acylguanidine FXa inhibitors.

A series of acylguanidine derivatives were prepared and investigated as inhibitors of Factor Xa (FXa). These compounds were made by guanidine acylation with carboxylic acids using carbonyl diimidazole (CDI) as the coupling reagent. Conditions for the rapid synthesis and purification of these compounds are described along with their ability to inhibit FXa.

Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors.

The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.

Ketene aminal-based lactam derivatives as a novel class of orally active FXa inhibitors.

N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.

Solution and Solid-State Studies of a Chiral Zinc-Sulfonamide Complex Relevant to Enantioselective Cyclopropanations.

A highly distorted tetrahedron formed by the four nitrogen atoms around zinc in the crystalline zinc-sulfonamide complex 1 may explain its catalytic activity in asymmetric cyclopropanations. The agent is formed by deprotonation of (R,R)-N,N'-cyclohexane-1,2-diyl)bis(n-butanesulfonamide) with diethylzinc and addition of 2,2'-bipyridyl.

Enantioselective Cyclopropanation of Allylic Alcohols. The Effect of Zinc Iodide.

The effect of zinc iodide on the catalytic, enantioselective cyclopropanation of allylic alcohols is examined with bis(iodomethyl)zinc as the reagent and bis-methanesulfonamide 7 as the catalyst. Significant rate enhancement was observed when 1 equiv of zinc iodide was present, but more importantly, the enantiomeric excess of the product cyclopropane increased from 80% to 89% for the substrate cinnamyl alcohol. Reaction studies and spectroscopic investigations show that this remarkable influence is the result of reagent modification via a Schlenk equilibrium that produces the more reactive and selective species (iodomethyl)zinc iodide.

Catalytic, Enantioselective Cyclopropanation of Allylic Alcohols. Substrate Generality.

Catalytic, enantioselective cyclopropanation of a broad range of allylic alcohols and one homoallylic alcohol was carried out. The cyclopropanation reagent employed was bis(iodomethyl)zinc generated by the method of Furukawa, and the chiral promoter used (10 mol %) was the N,N-bis(methanesulfonyl) derivative of (R,R)-1,2-diaminocyclohexane. Three experimental features were found to be critical for the rapid and selective cyclopropanation: (1) use of the ethylzinc alkoxide of the allylic alcohol as the substrate by prior deprotonation of the allylic alcohols by diethylzinc, (2) the formation of the zinc complex of the promoter by prior deprotonation of the bis-sulfonamide with diethylzinc, and (3) the use of added zinc iodide generated in situ from diethylzinc and iodine.