Prasun K. Chakravarty

Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.

Discovery of a potent and selective small molecule hGPR91 antagonist

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 μM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.

The synthesis of (2S,4S,5S) -5-(N-BOC)-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid lactone, an hydroxyethylene dipeptide isostere precusor

Abstract A synthetic approach to the butyrolactones of (2SR,4SR)-5(S)-(N-Boc)-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid from (L)-phenylalanine and the preparation of the n-butyl amide of the 2(S),4(S),5(S) acid is presented.

A potent and selective indole N-type calcium channel (Cav2.2) blocker for the treatment of pain

N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.

Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain.

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

Discovery of a novel class of biphenyl pyrazole sodium channel blockers for treatment of neuropathic pain.

A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.

An efficient synthesis of γ-amino-β-ketoalkylphosphonates from α-amino acids

Abstract The reaction of lithium salts of dialkyl methylphosphonates with suitably protected amino acid methyl esters at low temperature, followed by removal of protecting groups in the presence of trimethylsilyl bromide provides an efficient method for the synthesis of the titled compounds.

Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium channel blockers.

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.

Quinazolinone biphenyl acylsulfonamides: a potent new class of angiotensin-II receptor antagonists

Abstract A new series of quinazolinone-based AT 1 selective antagonists, bearing acylsulfonamides (-SO 2 NHCOR) as the tetrazole bioisosteres, was evaluated. While AT 1 potencies remained similar to the tetrazole analogs, the AT 2 receptor affinities were significantly improved with the introduction of acylsulfonamide groups. Several of these antagonists displayed improved in vivo properties.

Substituted biaryl pyrazoles as sodium channel blockers.

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.