The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).
Transient-receptor-potential
melastatin 8 (TRPM8), the predominant
mammalian cold-temperature thermosensor, is a nonselective cation
channel expressed in a subpopulation of sensory neurons in the peripheral
nervous system, including nerve circuitry implicated in migraine pathogenesis:
the trigeminal and pterygopalatine ganglia. Genomewide association
studies have identified an association between TRPM8 and reduced risk
of migraine. This disclosure focuses on medicinal-chemistry efforts
to improve the druglike properties of initial leads, particularly
removal of CYP3A4-induction liability and improvement of pharmacokinetic
properties. A novel series of biarylmethanamide TRPM8 antagonists
was developed, and a subset of leads were evaluated in preclinical
toxicology studies to identify a clinical candidate with an acceptable
preclinical safety profile leading to clinical candidate AMG 333,
a potent and highly selective antagonist of TRPM8 that was evaluated
in human clinical trials.
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC 50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ 40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.
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