Harshad Kantilal Rami

Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist

Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.

Characterization of SB-705498, a Potent and Selective Vanilloid Receptor-1 (VR1/TRPV1) Antagonist That Inhibits the Capsaicin-, Acid-, and Heat-Mediated Activation of the Receptor

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N′-{2-[ethyl(3-methylphenyl)amino]ethyl}urea (SB-452533), which has now entered clinical trials. Using a Ca2+-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pKi = 7.6) with activity at rat (pKi = 7.5) and guinea pig (pKi = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC50 = 3 nM)-, acid (pH 5.3)-, or heat (50°C; IC50 = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.

Non thiazolidinedione antihyperglycaemic agents. 1: α-Heteroatom substituted β-phenylpropanoic acids

The 5-benzylthiazolidine-2,4-dione moiety of insulin sensitising antidiabetic agents can be replaced by a range of α-heteroatom functionalised β-phenylpropanoic acids. α-Oxy-carboxylic acids show potent antidiabetic activity and one compound, the α-ethoxyacid 15 (SB 213068), is one of the most potent antihyperglycaemic agents yet reported.

Non-thiazolidinedione antihyperglycaemic agents. Part 3 : The effects of stereochemistry on the potency of α-methoxy-β-phenylpropanoic acids

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

Non thiazolidinedione antihyperglycaemic agents. 2: α-Carbon substituted β-phenylpropanoic acids1

The thiazolidine-2,4-dione ring of insulin sensitising antidiabetic agents can be replaced by α-acyl-, α-alkyl- and α-(aralkyl)-carboxylic acids. Inclusion of an additional lipophilic moiety affords compounds 14 and 16, equipotent to BRL 48482.

Synthetic ligands for PPARγ - review of patent literature 1994 - 1999

The recent identification of the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) as a primary molecular target for the thiazolidine-2,4-dione (glitazone) class of antihyperglycaemic agents now used in the treatment of Type 2 diabetes has provided an opportunity to develop novel PPARγ pharmacophores. This review outlines the molecular pharmacology of the PPAR family of nuclear receptors and summarises recent patents disclosing medicinal chemistry strategies to identify new PPARγ agonists. We also critically evaluate complementary parallel approaches that target other PPAR subtypes. This may yield useful treatment for other metabolic disorders that, like Type 2 diabetes, are also characterised by an excess cardiovascular risk.

A simplified template approach towards the synthesis of a potent beta-3 adrenoceptor agonist at the human receptor

Abstract A simplified template approach was used to delineate the structural requirements for high potency and intrinsic activity of aryloxypropanolamines as agonists at the human beta-3 adrenoceptor. The information generated was used to prepare selective beta-3 adrenoceptor agonists.

Efficient synthesis of protected β-phenylethylamines, enantiomerically pure protected β-phenyl-α-benzylethylamines and β-phenyl-α-isopropylethylamines using organozinc chemistry

The β-aminoalkylzinc reagents 9a, 10 and 11 have been efficiently prepared using DMF as a solvent. Palladium-catalysed coupling of these reagents with substituted aryl iodides, under mild and convenient conditions, gives protected β-phenylethylamines 6 in 72–80% yield (three examples), enantiomerically pure protected β-phenyl-α-benzylethylamines 7 in 53–61% yield (four examples), and protected β-phenyl-α-isopropylethylamines 8 in 53–79% yield (four examples).

Stereoselective syntheses of protected β-hydroxy-α-amino acids using (arylthio)nitrooxiranes

The scope and limitations of a method for the stereocontrolled synthesis of a range of protected β-hydroxy-α-amino acids have been established. The method comprises condensation of a chiral, enantiomerically pure aldehyde 6 with (4-methylphenylthio)nitromethane 7 to form a 1-arylthio-1-nitroalkene 8; stereoselective epoxidation of this alkene with a metal alkyl peroxide; and stereospecific reaction of the arylthionitrooxirane with a nitrogen nucleophile to give an α-amino thioester. This method has been employed in the synthesis of protected derivatives of both diastereoisomers of threonine 1 and 2, and of β-hydroxyleucine 3 and 4 and a synthesis of the anti-diastereoisomer of β-phenylserine 5.