Leucine-rich repeat kinase 2 inhibitors: a review of recent patents (2011 - 2013).

INTRODUCTION: Leucine-rich repeat kinase 2 (LRRK2) is a large (2527 residues) complex multi-domain protein that has GTPase and kinase domains. Autosomal dominant missense mutations in LRRK2 have been found in individuals with Parkinson's disease (PD) and are considered responsible for 1% of all cases of PD. Among the mutations confirmed to contribute to PD pathogenicity, G2019S is the most common cause of PD and it increases the kinase activity of LRRK2 by around threefold. LRRK2 has received considerable attention as a therapeutic target for PD, and LRRK2 inhibitors may help prevent and/or treat the disease. AREAS COVERED: LRRK2 inhibitors are being investigated by various industrial and academic institutions. The present review covers patents literature on small-molecule LRRK2 inhibitors patented between 2011 and 2013. EXPERT OPINION: Currently, wild-type and mutant LRRK2 are being examined as therapeutic targets for PD. In testimony to the significance of these novel targets, over 20 patent applications related to LRRK2 have been filed in the last 3 years. Several distinct chemotypes have been reported to be LRRK2 inhibitors with very good potency. These compounds are being used to elucidate the physiological and pathophysiological functions of LRRK2, and some may even emerge as therapeutics for PD.

Transient receptor potential A1 modulators.

TRPA1 is a member of a superfamily of non-selective cation channels that is known to be involved in multiple physiological functions. TRPA1 is activated by a broad spectrum of chemical irritants and endogenous inflammatory compounds. An emerging role for TRPA1 in mediating pain and inflammation raises the possibility that compounds targeting TRPA1 might have significant therapeutic potential. This review discusses the broad classes of molecules that are known to act as agonists and antagonists of TRPA1 towards the aim of providing an overview of the structure and activity of TRPA1 modulators.

Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.

Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.

Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution.

A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.

From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist.

Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.

Pharmacological characterization of a novel nonpeptide antagonist radioligand, (+/-)-N-[2-methyl-4-methoxyphenyl]-1-(1-(methoxymethyl) propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine ([3H]SN003) for corticotropin-releasing factor1 receptors.

The in vitro pharmacological profile of a novel small molecule corticotropin-releasing factor 1 (CRF(1)) receptor antagonist, (+/-)-N-[2-methyl-4-methoxyphenyl]-1-(1-(methoxymethyl)propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine (SN003), and the characteristics of its radioligand ([(3)H]SN003) are described. SN003 has high affinity and selectivity for CRF(1) receptors expressed in rat cortex, pituitary, and recombinant HEK293EBNA (HEK293e) cells with respective radiolabeled ovine CRF ([(125)I]oCRF) binding K(i) values of 2.5, 7.9, and 6.8 nM. SN003 was shown to be a CRF(1) receptor antagonist inasmuch as it inhibited CRF-induced cAMP accumulation in human CRF(1)HEK293e cells and CRF-stimulated adrenocorticotropin hormone release from rat pituitary cells without agonist activities. Significant decreases in the B(max) of [(125)I]oCRF binding by SN003 suggest that this antagonist is not simply competitive. To further explore the interaction of SN003 with the CRF(1) receptors, [(3)H]SN003 binding to rat cortex and human CRF(1)HEK293e cell membranes was characterized and shown to be reversible and saturable, with K(D) values of 4.8 and 4.6 nM, and B(max) values of 0.142 and 7.42 pmol/mg protein, respectively. The association and dissociation rate constants of [(3)H]SN003 (k(+1) 0.292 nM(-1) min(-1) and k(-1) 0.992 x 10(-2) min(-1)) were also assessed using human CRF(1)HEK293e cell membranes, giving an equilibrium dissociation constant of 3.4 nM. Moreover, [(3)H]SN003 binding displayed a single affinity state and insensitivity to 5'-guanylylimidodiphosphate, consistent with characteristics of antagonist binding. Incomplete inhibition of [(3)H]SN003 binding by CRF peptides also suggests that SN003 is not simply competitive with CRF at CRF(1) receptors. The distribution of [(3)H]SN003 binding sites was consistent with the expression pattern of CRF(1) receptors in rat brain regions. Small molecule CRF(1) antagonist radioligands like [(3)H]SN003 should enable a better understanding of small molecule interactions with the CRF(1) receptor.