title: Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties.
abstract: Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>or=200 microg/mL in 0.01 N HCl) and a reduced half-life (rat t1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. huiw@amgen.com
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.forename: Jodie
authors.initials: J
authors.lastname: Katon
authors.forename: Chenera
authors.initials: C
authors.lastname: Balan
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: Charles
authors.initials: C
authors.lastname: Bernard
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Vijay
authors.initials: V
authors.lastname: Gore
authors.forename: Vu
authors.initials: V
authors.lastname: Ma
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Phi
authors.initials: P
authors.lastname: Tang
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Oliver
authors.initials: O
authors.lastname: Thiel
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004355:Drug Stability; D000882:Haplorhini; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D010147:Pain Measurement; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D013816:Thermodynamics
chemical_list: D000700:Analgesics; D052160:Benzothiazoles; C523410:N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo(d)thiazol-2-yl)acetamide; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat