Prabhakar K. Jadhav

Flexibility and function in HIV-1 protease

HIV protease is a homodimeric protein whose activity is essential to viral function. We have investigated the molecular dynamics of the HIV protease, thought to be important for proteinase function, bound to high affinity inhibitors using NMR techniques. Analysis of 15N spin relaxation parameters, of all but 13 backbone amide sites, reveals the presence of significant internal motions of the protein backbone. In particular, the flaps that cover the proteins active site of the protein have terminal loops that undergo large amplitude motions on the ps to ns time scale, while the tips of the flaps undergo a conformational exchange on the μs time scale. This enforces the idea that the flaps of the proteinase are flexible structures that facilitate function by permitting substrate access to and product release from the active site of the enzyme.

Synthesis of 7-membered cyclic oxamides: Novel HIV-1 protease inhibitors

Abstract An intermediate with three chiral centers, constructed by two key reactions viz. asymmetric allylboration and Sharpless epoxidation, has been used for the synthesis of novel 7-membered cyclic oxamides.

Synthesis of 8-membered cyclic sulfamides: Novel HIV-1 protease inhibitors

Abstract One pot synthesis of pseudo C2 symmetric (2S,6S)-2,6-dihydroxy-1,7-diphenylhept-4-one in high enantiomeric purity has been developed and the intermediate was used for the synthesis of 8-membered cyclic sulfamides.

αvβ3 integrin binding affinity and specificity of SM256 in various species

This study was undertaken to define the alphavbeta3 binding affinity and specificity of the low-molecular-weight nonpeptide integrin antagonist, SM256. SM256 demonstrated high potency (IC50, 0.057+/-0.030 nM) in inhibiting vitronectin binding to purified human alphavbeta3 receptors. Additionally, SM256 inhibited alphavbeta3-mediated human umbilical vein endothelial cell (HUVEC) or 293/beta3 (beta3-transfected cell line) adhesion to fibrinogen with IC50 values of 0.0054+/-0.0058 and 0.0023+/-0.0012 microM, respectively. SM256 demonstrated a relatively high degree of specificity for human alphavbeta3-mediated functions as compared with other human integrins including alphavbeta5 (IC50, 0.92+/-0.69 microM), alphaIIbbeta3 (IC50, 0.72+/-0.07 microM), alpha4/beta1 (IC50, >100 microM) and alpha5/beta1 (IC50, 2.3+/-2.1 microM). SM256 demonstrated different degree of species specificity in blocking alphavbeta3-mediated cellular adhesion with relatively higher affinity to dog (IC50, 0.005+/-0.002 microM), rabbit (IC50, 0.021+/-0.01 microM), mouse (IC50, 0.035+/-0.01 microM), and pig (IC50, 0.41+/-0.24 microM) endothelial or smooth-muscle cell alphavbeta3-mediated adhesion. Additionally, SM256 demonstrated high degree of alphavbeta3 specificity as compared with alphavbeta5, alpha5beta1, or alphaIIbbeta3-mediated binding in these species. SM256 is a potent alphavbeta3, antagonist with high affinity and specificity for alphavbeta3-mediated functions. Additionally, a comparable alphavbeta3 affinity for SM256 was demonstrated with endothelial cells obtained from various species (dog, mouse, rabbit, and pig) as compared with that from human.

Rapid synthesis of RGD mimetics with isoxazoline scaffolds on solid phase: Identification of αvβ3 antagonists lead compounds

Isoxazoline containing RGD mimetics were rapidly synthesized on a solid phase to optimize linkers, regioisomers of isoxazoline scaffolds, and exosite binding groups to yield lead αvβ3 antagonists.

Potentially general synthesis of polyhyroxyindolizidines

Abstract Allylboration of pentose derivatives with (Z)-3-(methoxy)methoxyallyldiisopinocampheylboranes provides octose derivatives with excellent diastereoselectivity. These intermediates are efficiently utilized for the synthesis of polyhydroxyindolizidines.

2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy.

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.

De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule

Combining the Caco-2 cell assay, dog pharmacokinetic assessment on selected compounds, antiviral testing against wild-type and mutant variants, and antiviral testing in the presence of human plasma proteins, we can define the overall quality of a given compound. We can then select compounds for further preclinical evaluation.

Asymmetric synthesis of (3R)-alkanoyloxytetradecanoic acids-components of bacterial lipopolysaccharides

Abstract An efficient general synthesis of (3R)-alkanoyloxytetradecanoic acids has been developed by asymmetric allylboration, acylation followed by oxidation of the homoallylic esters.

Synthesis of water soluble prodrug of DMP323

Abstract A water soluble bisphosphate prodrug of DMP323 was synthesized from DMP323. Pharmacokinetic studies of the prodrug indicate that it is orally absorbed as the parent drug, after hydrolysis of the phosphate ester in the gastrointestinal tract.