Ashok Kumar Gangopadhyay

Synthesis and biological evaluation of isoxazole, oxazole, and oxadiazole containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

Diacylglycerol acyltransferase, DGAT1, is a promising target enzyme for obesity due to its involvement in the committed step of triglyceride biosynthesis. Amino biphenyl carboxylic acids, exemplified by compound 4, are known potent inhibitors of hDGAT1. However the high cLogP and poor solubility of these biphenyl analogs might tend to limit their development. We have synthesized and evaluated compounds containing 3-phenylisoxazole, 5-phenyloxazole, and 3-phenyl-1,2,4-oxadiazole biaryl units for their hDGAT1 inhibition. Our aim in synthesizing such heterocyclic analogs was to improve the cLogP and solubility of these molecules while retaining hDGAT1 potency. Several compounds within the 3-phenylisoxazole series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Certain promising compounds were studied for their potential to reduce triglyceride levels using an in vivo fat tolerance test in mice and were also evaluated for any possible improvement to their solubility. Compound 40a (IC(50) = 64 nM) with an in vivo plasma triglyceride reduction of 90 percent, and a solubility of 0.43 mg/ml at pH 7.4 may serve as a new lead for developing newer anti-obesity agents.

Hydroxyacyl derivatives of forskolin--their positive inotropic activity.

Using appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH2)nOH are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive inotropic activity. Compound 12 is almost 10 times more active than forskolin (EC50 = 0.002 microgram/ml).].

IN SEARCH OF NOVEL WATER SOLUBLE FORSKOLIN ANALOGUES FOR POSITIVE INOTROPIC ACTIVITY

Using the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7 beta-hydroxyacetyl-7 beta-deacetyl forskolin or 6 beta-hydroxyacetyl forskolin, a number of water soluble omega-amino acyl derivatives were synthesized. Two such compounds 6 and 18 showed better in vitro activity but failed to show in vivo activity.

Novel Chiral Auxiliary for Attempted Resolution of Key Roxifiban Intermediate: A Simple Diastereoselective Coupling Approach for the Synthesis of Roxifiban

Abstract This article describes a simple method for the synthesis of roxifiban, a potent glycoprotein GP IIb‐IIIa receptor antagonist, by a diastereoselective coupling approach to give >99.9% optical purity. We have also described an attempt to resolve the key synthetic intermediate by diastereomeric ester formation. Although we have been able to separate two diastereomeric esters, the removal of the chiral auxiliary led to partial racemization.

A Novel Chemo‐selective Epoxidation across Acrylate Ester: Synthesis of New Water‐Soluble Forskolin Analogues

Abstract While removing the TBDMS group from OH protection, a novel epoxidation reaction occurred across acrylate ester attached to a forskolin fragment. Besides spectroscopic data, the epoxide formation was confirmed by ring opening with a secondary amine. This unique epoxidation reaction, to our knowledge, is not known in the literature. This reaction led us to discover a simple deblocking protocol. The epoxide and the desired Michael substrates were used to introduce imidazole into forskolin.

New Ion‐Exchange cum Separation Technique: A Study for the Synthesis of ω‐Guanidine containing Peptides using ω‐Amino Acid as Surrogate

Abstract This article describes a systematic study for the introduction of ω‐guanidine function at a late stage of synthesis using a protected amino group as a surrogate to improve overall yield. This concept was used to design and synthesize pseudo‐peptides as GP IIb–IIIa receptor antagonist wherein glycine in endogenous ligand Arg‐Gly‐Asp (RGD) is replaced by 2‐amino‐thiazole‐4‐ylacetic acid (Tha) as a spacer. Further, we describe here a unique salt exchange cum purification technology based on reverse phase (RP‐18) medium‐pressure liquid chromatography.

Forskolin and 7-deacetylforskolin : study of the reactivity behaviour towards different phosphorylating agents

Reaction of different phosphorylating agents such as POCl3, bis-(p-methoxyphenyl) phosphorochloridate, 2-chloro-2-oxo-1,3,2-dioxaphospholane and bis-(trifluoroethyl) phosphite with forskolin gave the corresponding isomers α- and β-1, 9-cyclic phosphates/phosphites. 1,2-Dibromo-2-phenylethylphosphonic acid reacted with forskolin and 7-deacetylforskolin to give forskolin 1-phosphate 17 and 7-deacetylforskolin 7-phosphate 18, respectively.