title: The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2.
abstract: Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).
authors: Department of Molecular Sciences and Candidate Optimization (MSCO), Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiaojun.han@bms.com
authors: Xiaojun
authors: X
authors: Han
authors: Rita L
authors: RL
authors: Civiello
authors: Charles M
authors: CM
authors: Conway
authors: Deborah A
authors: DA
authors: Cook
authors: Carl D
authors: CD
authors: Davis
authors: Andrew P
authors: AP
authors: Degnan
authors: Xiang-Jun
authors: XJ
authors: Jiang
authors: Robert
authors: R
authors: Macci
authors: Neil R
authors: NR
authors: Mathias
authors: Paul
authors: P
authors: Moench
authors: Sokhom S
authors: SS
authors: Pin
authors: Richard
authors: R
authors: Schartman
authors: Laura J
authors: LJ
authors: Signor
authors: George
authors: G
authors: Thalody
authors: George
authors: G
authors: Tora
authors: Valerie
authors: V
authors: Whiterock
authors: Cen
authors: C
authors: Xu
authors: John E
authors: JE
authors: Macor
authors: Gene M
authors: GM
authors: Dubowchik
mesh_terms: D000281:Administration, Intranasal; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006207:Half-Life; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D001583:Benzoxazoles; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007191:Indazoles; D052999:Quinazolinones; D018015:Receptors, Calcitonin Gene-Related Peptide; C017057:benzoxazolone; D014443:Tyrosine